Cdk2 inhibitors

ABSTRACT

The present disclosure provides a compound represented by structural Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof useful for treating a cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Pat. ApplicationNo. 17/850,453, filed on Jun. 27, 2022, which claims the benefit of andpriority to U.S. Provisional Pat. Application No. 63/215,901, filed onJun. 28, 2021, the disclosure of each of which is hereby incorporated byreference in its entirety for all purposes.

BACKGROUND

Cyclin-Dependent Kinase (CDK) are serine/threonine protein kinases thathave a central role in cell cycle progression. CDK levels remainrelatively constant throughout the cell cycle, and it is the selectiveactivation of specific CDKs allows for the proper ordering of the stepsin cell cycle progression. Activation of CDKs requiresheterodimerization with regulatory subunits known as cyclins. Cell cyclederegulation is a common feature of human cancer.

Cyclin-dependent kinase 2 (Cdk2) participates in a range of biologicalactivities. CDK2 is a key cell cycle regulator, active from the lateGi-phase and throughout the S-phase. CDK2 is involved in DNA damageresponse (DDR) through the homologous recombination (HR) pathway. CDK2also regulates aspects of apoptotic pathways. Cyclin E1 (CCNE1), cyclinE2 (CCNE2), cyclin A1 (CCNA1), and cyclin A2 (CCNA2), along withp21Cip1/Waf1, p27Kip1 and p57Kip2 (the cyclin dependent kinaseinhibitors of the cyclin-CDK2 complex) are the main regulators of CDK2activity. In cancer, dysregulation of the binding of CDK2 by cyclin E1,E2, A1, or A2 or the activity of the cyclin-dependent kinase inhibitorproteins may occur. (See S. Tadesse et al., Drug Discovery Today, Volume25, Number 2 Feb. 2020)

The dysregulation of CDK2 can occur through several mechanisms.Amplification and/or overexpression of CCNE1 has been identifiedoccurring in ovarian and breast cancer (See Scaltriti, M. et al., Proc.Natl Acad. Sci. USA 108, 3761-3766 (2011) and Etemadmoghadam, D. et al.Proc. Natl Acad. Sci. USA 110, 19489-19494 (2013). Poor outcomes ingastric, endometrial, and other cancers have been associated withoverexpression and/or amplification of CCNE1 (See Ooi et al. Hum Pathol.(2017) 61:58-67, and Noske et al, Oncotarget (2017) 8: 14794-14805).

While these findings indicate CDK2 is a potential target for cancerswith deregulated CDK2 activity, no agents selectively targeting CDK2have been approved to date. Therefore, there is a need to develop newCDK2 inhibitors.

SUMMARY

The applicant has discovered novel compounds which are effectiveinhibitors of CDK2 (see Synthetic Examples 1-227). In particular, it hasbeen demonstrated that the compounds of the present disclosureeffectively inhibit CDK2. Compounds of the disclosure (also referred toherein as the “disclosed compounds”) or pharmaceutically acceptablesalts thereof effectively inhibit CDK2. (see Biological Example 1) andcan be used treat various cancers. Importantly, the disclosed compoundsare selective CDK2 inhibitors, i.e., the disclosed compounds have no orlow activity against CDK-family kinases, most notably CDK1. Advantagesassociated with such selectivity may include facilitating efficaciousdosing and reducing CDK1-mediated on-target toxicities. Some of thedisclosed compounds also have the advantage of having high microsomalstability. Compounds of the disclosure also may have favorable toxicityprofiles related to other non-kinase targets.

In one aspect, the present disclosure provides a compound represented bythe following structural Formula (I):

or a pharmaceutically acceptable salt thereof, the definition of eachvariable is provided below.

In another aspect, the present disclosure provides a compoundrepresented by the following structural Formula (Ia):

or a pharmaceutically acceptable salt thereof, the definition of eachvariable is provided below.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier or diluentand one or more of the compounds disclosed herein, or a pharmaceuticallyacceptable salt thereof (a “pharmaceutical composition of thedisclosure”).

The present disclosure provides a method of treating a subject withcancer, comprising administering to the subject an effective amount of acompound of the disclosure (e.g., a compound of Formula (I) or Formula(Ia)) or a pharmaceutically acceptable salt thereof or a pharmaceuticalcomposition of the disclosure. In one embodiment, the cancer is uterinecancer (including uterine carcinosarcoma (UCS), uterine corpusendometrial carcinoma (UCEC)), endometrial cancer, breast cancer(including breast invasive carcinoma (BRCA), TNBC (triple negativebreast cancer), HR+ breast cancer (hormone receptor positive breastcancer), ER+ breast cancer (estrogen receptor positive breast cancer),HR+HER2- breast cancer (hormone receptor positive, human epidermalgrowth factor 2 negative breast cancer), ER+HER2- breast cancer(estrogen receptor positive, human epidermal growth factor 2 negativebreast cancer), HER2- breast cancer (human epidermal growth factor 2negative breast cancer), HER2-low breast cancer (human epidermal growthfactor 2 low breast cancer), and HER2+ breast cancer (human epidermalgrowth factor 2 positive breast cancer), ovarian cancer (e.g. ovarianserous cystadenocarcinoma (OV)), stomach cancer (including stomachadenocarcinoma (STAD)), gastric cancer (including gastrointestinalstromal tumor), colorectal cancer, pancreatic cancer (includingpancreatic adenocarcinoma (PAAD), kidney cancer, head and neck cancer,liver cancer, prostate cancer, skin cancer, leukemia (including AML(acute myeloid leukemia)), lymphoma (including B-cell lymphoma),myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN),sarcoma (SARC), esophageal cancer (including esophageal carcinoma(ESCA)), bladder cancer (including bladder urothelial carcinoma), lungcancer (including lung squamous carcinoma and non-small cell lungcancer, e.g., EGFRm (epidermal growth factor receptor mutant)+ non-smallcell lung cancer), cholangiocarcinoma, adrenocortical carcinoma (ACC),or mesothelioma. In some embodiments, the cancer is breast cancer. Inone embodiment, the subject has CCNE1 amplified advanced/relapsedtumors. In one embodiment, the subject has CCNE1 amplifiedplatinum-resistant or platinum-refectory ovarian cancer. In oneembodiment, the subject has endometrial cancer (with prior platinumtherapy, e.g., wherein the patient has been previously treated with aplatinum therapy) that has progressed following 2 or more lines oftherapies (including the platinum therapy). In one embodiment, thesubject has CCNE1 amplified endometrial cancer that has failed 2 or morelines of therapies (which may include a prior platinum therapy). In oneembodiment, the subject has gastric cancer (with prior platinum therapye.g., wherein the patient has been previously treated with a platinumtherapy) that has progressed following 2 or more lines of therapies(including the platinum therapy). In one embodiment, the subject has ER+HER- breast cancer that has progressed despite treatment with one ormore CDK4/6 inhibitors.

In one embodiment, the cancer as described herein to be treated (e.g.,the cancer as described in paragraphs [0010], [0020], [0120]-[0129],[0131], and [0133]-[0148], e.g., breast cancer) has CCNE1 amplificationand/or overexpression.

In one embodiment, the cancer as described herein to be treated (e.g.,the cancer as described in paragraphs [0010], [0020], [0120]-[0129],[0131], and [0133]-[0148], e.g., breast cancer) does not have a CCNE1amplification and/or overexpression.

The treatment method disclosed herein further comprises administering tothe subject an effective amount of palbociclib (e.g., ibrance®),ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g.,lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine,megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g.,xeloda®), regorafenib (e.g., stivarga®), afatinib (e.g., gilotrif®),osimertinib (e.g., tagrisso®), gefitinib (e.g., iressa®), erlotinib(e.g., tarceva®), ramucirumab (e.g., cyramza®), an EGFR inhibitor,pralsetinib, ABT-263 (navitoclax), MK-1775 (adavosertib), BAY-1895344,berzosertib, ceralasertib, SRA-737, LY2603618 (rabusertib), ortrastuzumab (e.g., herceptin®), or combinations thereof. The EGFRinhibitor may be selected from afatinib, osimertinib, lapatinib,erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02,alflutinib (AST 2818), aumolertinib (formerly almonertinib) (HS10296),BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilitertinib,icotinib, JND-3229, lazertinib, nazartinib (EGF 816), avitinib,PCC-0208027, rezivertinib (BPI-7711), TQB3804, zorifertinib (AZ-3759),or DZD9008; an EGFR antibody such as cetuximab, panitumumab,necitumumab, HLX07, JMT101; or a bispecific EGFR and MET antibody (e.g.,amivantamab ((JNJ-61186372, JNJ-372)).

The present disclosure also provides a method of inhibiting CDK2 in asubject in need thereof, comprising administering to the subject aneffective amount of a compound of the disclosure (e.g., a compound ofFormula (I) or Formula (Ia)) or a pharmaceutically acceptable saltthereof or a pharmaceutical composition of the disclosure.

The present disclosure also provides the use of an effective amount of acompound of the disclosure (e.g., a compound of Formula (I) or Formula(Ia)), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of the disclosure, for the preparation of amedicament for the treatment of cancers.

In another aspect, provided herein is a compound of Formula (I) orFormula (Ia), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of the disclosure for use in treatingcancers.

In one aspect, the present disclosure provides a method of treating asubject having, or at risk of developing, a disease or disorderassociated with CDK2, comprising administering to the subject atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition disclosed herein, wherein the subject has an amplificationof the CCNE1 gene and/or have an expression level of CCNE1 higher than acontrol expression level of CCNE1. In some embodiments, the disease ordisorder associated with CDK2 is cancer.

The present disclosure also provides a method of treating a subjecthaving, or at risk of developing, a disease or disorder associated withCDK2, comprising administering to the subject a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition disclosedherein, wherein the subject has an amplification of the CCNE1 geneand/or have an expression level of CCNE1 similar to a control expressionlevel of CCNE1. In some embodiments, the disease or disorder associatedwith CDK2 is cancer.

Also provided herein is a method of treating a patient having anamplified expression level of CCNE1 and suffering from, or at risk ofdeveloping, a solid tumor cancer, comprising administering to thepatient a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition disclosed herein.

The contemplated solid tumor cancer may be at least one of: uterinecancer (including uterine carcinosarcoma, uterine corpus endometrialcarcinoma (UCEC)), endometrial cancer, breast cancer (including breastinvasive carcinoma, TNBC (triple negative breast cancer), ER (estrogenreceptor)+HER2 (human epidermal growth factor 2)-breast cancer, HR(hormone receptor)+HER2 (human epidermal growth factor 2)- breastcancer, HER2- breast cancer and HER2+ breast cancer), ovarian cancer(e.g. ovarian serous cystadenocarcinoma), stomach cancer (includingstomach adenocarcinoma), gastric cancer (including gastrointestinalstromal tumor), colorectal cancer, pancreatic cancer, kidney cancer,head and neck cancer, liver cancer, prostate cancer, skin cancer,lymphoma (including B-cell lymphoma), sarcoma, esophageal cancer(including esophageal carcinoma and esophageal adenocarcinoma), bladdercancer (including bladder urothelial carcinoma (BLCA)), lung cancer(including lung squamous carcinoma and non-small cell lung cancer, e.g.,EGFRm (epidermal growth factor receptor mutant)+ non-small cell lungcancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma.

DETAILED DESCRIPTION Definitions

The term “halo” as used herein means halogen and includes chloro,fluoro, bromo and iodo.

The term “alkyl” used alone or as part of a larger moiety, such as“alkoxy” or “haloalkyl” and the like, means saturated aliphaticstraight-chain or branched monovalent hydrocarbon radical. Unlessotherwise specified, an alkyl group typically has 1-4 carbon atoms, i.e.(C₁-Ca)alkyl. As used herein, a “(C₁-C₄)alkyl” group means a radicalhaving from 1 to 4 carbon atoms in a linear or branched arrangement.Examples include methyl, ethyl, n-propyl, iso-propyl, and the like.

The term “alkoxy” means an alkyl radical attached through an oxygenlinking atom, represented by -O-alkyl. For example, “(C₁-C₄)alkoxy”includes methoxy, ethoxy, propoxy, and butoxy.

The term “cycloalkyl” refers to a monocyclic saturated hydrocarbon ringsystem. Unless otherwise specified, cycloalkyl has from 3-10 carbonatoms. In some embodiments, cycloalkyl has from 3-6 carbon atoms. Forexample, a C₃-C₁₀ cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Unless otherwise described, a “cycloalkyl”has from three to ten carbon atoms.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 4- to12-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, andsulfur, including sulfoxide and sulfone (“4-12 membered heterocyclyl).In some embodiments, heterocyclyl is a 3- to 6- membered non-aromaticring system having ring carbon atoms and 1 to 4 ring heteroatoms,wherein each heteroatom is independently selected from nitrogen,quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur,including sulfoxide and sulfone. In some embodiment, hetrocyclyl has 1to 2 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO),oxygen, and sulfur, including sulfoxide and sulfone. In heterocyclylgroups that contain one or more nitrogen atoms, the point of attachmentcan be a carbon or nitrogen atom, as valency permits. Exemplaryheterocyclyl groups include azetidinyl, oxetanyl, thietanyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl,piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl,tetrahydropyridinyl, and the like.

The term “heteroaryl” refers to a radical of a 4-12 membered monocyclicor bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” also includesring systems wherein the heteroaryl ring, as defined above, is fusedwith one or more aryl groups wherein the point of attachment is eitheron the aryl or heteroaryl ring, and in such instances, the number ofring members designates the number of ring members in the fused(aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein onering does not contain a heteroatom (e.g., indolyl, quinolinyl,carbazolyl, and the like) the point of attachment can be on either ring,i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ringthat does not contain a heteroatom (e.g., 5-indolyl). A heteroaryl groupmay be described as, e.g., a 6-10-membered heteroaryl, wherein the term“membered” refers to the non-hydrogen ring atoms within the moiety

It will be apparent to one skilled in the art that certain compoundsdisclosed herein may exist in tautomeric forms, all such tautomericforms of the compounds being within the scope of the disclosure. Theterm “tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H).

Compounds of the Present Disclosure

Disclosed herein are embodiments of compounds having a general structureof Formula (I) or Formula (Ia). The present invention provides acompound of the present invention or a pharmaceutically acceptable saltthereof for use in the treatment of cancer. These compounds areselective inhibitors of CDK2.

In a first embodiment, the present disclosure provides a compoundrepresented by the following structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

-   R¹ is C₁-C₄alkyl optionally substituted with 1 to 4 halo;-   R² is C₁-C₄alkyl or Ring A, wherein the C₁-C₄alkyl is optionally    substituted with 1 to 4 groups each independently selected from    halo, CN, and OH and/or 1 group of 5 to 6 membered heteroaryl having    1 to 3 ring heteroatoms each independently selected from the group    consisting of O, S and NR^(d); and-   R³ is selected from the group consisting of H, C₁-C₄alkyl,    C₃-C₁₀cycloalkyl, and 4 to 12-membered heterocyclyl, wherein the    C₁-C₄alkyl and C₃-C₁₀cycloalkyl are each optionally substituted with    1 to 4 R^(C), wherein the 4 to 12-membered heterocyclyl has 1 to 4    ring heteroatoms each independently selected from the group    consisting of O, S and NR^(d) and then is optionally substituted on    a ring carbon with 1 to 4 R^(C); or-   R² and R³ are taken together with the carbon atom to which they are    attached to form Ring B, wherein Ring B is C₃-C₁₀cycloalkyl or 4 to    12- membered heterocyclyl, wherein the C₃-C₁₀cycloalkyl is    optionally substituted with 1 to 4 R^(b), wherein the 4 to 12-    membered heterocyclyl has 1 to 4 ring heteroatoms each independently    selected from the group consisting of NR^(d), O, and S and then is    optionally substituted on a ring carbon by 1 to 4 R^(b);-   Ring A is selected from the group consisting of C₃-C₁₀cycloalkyl,    phenyl, naphthyl, 4 to 12-membered heterocyclyl, and 4 to    12-membered heteroaryl, wherein the C₃-C₁₀cycloalkyl, phenyl, and    naphthyl are each optionally substituted with 1 to 4 R^(a), wherein    the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl    have 1 to 4 ring heteroatoms each independently selected from the    group consisting of O, S and NR^(d) and then are optionally    substituted on a ring carbon with 1 to 4 R^(a);-   Each R^(a) is independently selected from the group consisting of    halo, OH, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, or two R^(a), attached to    the same atom, form a ═O, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are    each optionally substituted with 1 to 4 groups each independently    selected from the group consisting of halo, OH and CN;-   Each R^(b) is independently selected from the group consisting of    halo, OH, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, or two R^(b), attached to    the same atom, form a =O, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are    each optionally substituted with 1 to 4 groups each independently    selected from the group consisting of halo, OH and CN;-   Each R^(C) is independently selected from the group consisting of    halo, OH, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, or two R^(C), attached to    the same atom, form a ═O, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are    each optionally substituted with 1 to 4 groups each independently    selected from the group consisting of halo, OH, and CN; or-   Each R^(d) is independently H or C₁₋C₆alkyl;-   R⁴ is H or C₁-C₄alkyl optionally substituted with 1 to 4 groups each    independently selected from halo and OH; and-   R⁵ is selected from the group consisting of H, halo, CN, and    C₁-C₄alkyl, wherein the C₁-C₄alkyl is optionally substituted with 1    to 4 groups each independently selected from halo and OH.

In another embodiment, the present disclosure provides a compoundrepresented by the following structural formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein

-   R¹ is C₁-C₄alkyl optionally substituted with 1 to 4 groups each    independently selected from halo and D;-   R² is C₁-C₄alkyl or Ring A, wherein the C₁-C₄alkyl is optionally    substituted with 1 to 4 groups each independently selected from    halo, D, CN, and OH and/or 1 group of 5 to 6 membered heteroaryl    having 1 to 3 ring heteroatoms each independently selected from the    group consisting of O, S and NR^(d); and-   R³ is selected from the group consisting of H, D, C₁-C₄alkyl,    C₃-C₁₀cycloalkyl, and 4 to 12-membered heterocyclyl, wherein the    C₁-C₄alkyl and C₃-C₁₀cycloalkyl are each optionally substituted with    1 to 4 R^(C), wherein the 4 to 12-membered heterocyclyl has 1 to 4    ring heteroatoms each independently selected from the group    consisting of O, S, and NR^(d) and then is optionally substituted on    a ring carbon with 1 to 4 R^(C); or-   R² and R³ are taken together with the carbon atom to which they are    attached to form Ring B, wherein Ring B is C₃-C₁₀cycloalkyl or 4 to    12- membered heterocyclyl, wherein the C₃-C₁₀cycloalkyl is    optionally substituted with 1 to 4 R^(b), wherein the 4 to 12-    membered heterocyclyl has 1 to 4 ring heteroatoms each independently    selected from the group consisting of NR^(d), O, and S and then is    optionally substituted on a ring carbon by 1 to 4 R^(b);-   Ring A is selected from the group consisting of C₃-C₁₀cycloalkyl,    phenyl, naphthyl, 4 to 12-membered heterocyclyl, and 4 to    12-membered heteroaryl, wherein the C₃-C₁₀cycloalkyl, phenyl, and    naphthyl are each optionally substituted with 1 to 4 R^(a), wherein    the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl    have 1 to 4 ring heteroatoms each independently selected from the    group consisting of O, S, and NR^(d) and then are optionally    substituted on a ring carbon with 1 to 4 R^(a);-   Each R^(a) is independently selected from the group consisting of D,    halo, OH, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, or two R^(a), attached to    the same atom, form a ═O, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are    each optionally substituted with 1 to 4 groups each independently    selected from the group consisting of halo, OH and CN;-   Each R^(b) is independently selected from the group consisting of D,    halo, OH, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, or two R^(b), attached to    the same atom, form a ═O, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are    each optionally substituted with 1 to 4 groups each independently    selected from the group consisting of halo, OH and CN;-   Each R^(C) is independently selected from the group consisting of D,    halo, OH, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, or two R^(C), attached to    the same atom, form a ═O, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are    each optionally substituted with 1 to 4 groups each independently    selected from the group consisting of halo, OH, and CN; or-   Each R^(d) is independently selected from the group consisting of H,    D, and C₁₋C₆alkyl;-   R⁴ is selected from the group consisting of H, D, and C₁-C₄alkyl    optionally substituted with 1 to 4 groups each independently    selected from halo, D and OH;-   R⁵ is selected from the group consisting of H, D, halo, CN, and    C₁-C₄alkyl, wherein the C₁-C₄alkyl is optionally substituted with 1    to 4 groups each independently selected from halo and OH;-   R⁶ is H or D; and-   R⁷ is H or D.

In some embodiments, each R^(a) is independently selected from the groupconsisting of halo, OH, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, or two R^(a),attached to the same atom, form a ═O, wherein the C₁-C₄alkyl andC₁-C₄alkoxy are each optionally substituted with 1 to 4 groups eachindependently selected from the group consisting of halo, OH and CN;each R^(b) is independently selected from the group consisting of halo,OH, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, or two R^(b), attached to the sameatom, form a ═O, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are eachoptionally substituted with 1 to 4 groups each independently selectedfrom the group consisting of halo, OH and CN; each R^(C) isindependently selected from the group consisting of halo, OH, CN,C₁-C₄alkyl, and C₁-C₄alkoxy, or two R^(C), attached to the same atom,form a =O, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are each optionallysubstituted with 1 to 4 groups each independently selected from thegroup consisting of halo, OH, and CN; or each R^(C) is independently Hor C₁₋C₆alkyl.

In some embodiments, R² is C₁-C₄alkyl or Ring A, wherein the C₁-C₄alkylis optionally substituted with 1 to 4 groups each independently selectedfrom halo, CN, and OH and/or 1 group of 5 to 6 membered heteroarylhaving 1 to 3 ring heteroatoms each independently selected from thegroup consisting of O, S and NR^(d); or R⁴ is selected from the groupconsisting of H, D, and C₁-C₄alkyl optionally substituted with 1 to 4groups each independently selected from halo and OH.

In some embodiments, R¹ is methyl or ethyl, each optionally substitutedwith 1 to 4 halo.

In some embodiments, R¹ is methyl or ethyl, each optionally substitutedwith 1 to 4 halo or D.

In some embodiments, R¹ is selected from the group consisting of methyl,ethyl, CF₃, CH₂F, and CHF₂.

In some embodiments, R¹ is selected from the group consisting of methyl,ethyl, CD₃, CD₂H, CDH₂, CF₃, CH₂F, and CHF₂.

In some embodiments, R¹ is CHF₂.

In some embodiments, R¹ is CD₃.

In some embodiments, R² is selected from the group consisting of Ring A,methyl, ethyl, CH(OH)CH₃, CH₂F, CHF₂, CH₂OH, CH(CH₃)CH2OH, CH₂,CH₂OH,

In some embodiments, Ring A is selected from the group consisting of :

In some embodiments, R^(a) is selected from the group consisting offluoro, chloro, CN, OH, OCH₃, methyl, CH₂CN, CF₃, and CHF₂; or twoR^(a), attached to the same atom, form a ═O.

In some embodiments, R³ is selected from the group consisting of H,methyl, ethyl, CH(OH)CH₃, CH₂F, CHF₂, CH₂OH, CH(CH₃)CH2OH, CH₂,CH₂OH,

In some embodiments, R° is selected from OH and F.

In some embodiments, Ring B is selected from the group consisting of:

In some embodiments, R^(b) is selected from the group consisting of OH,F, and CH₂OH.

In some embodiments, R⁴ is selected from the group consisting of H,methyl, and ethyl, CH(OH)CH₃, CH₂F, CHF₂, CH₂OH, CH(CH₃)CH2OH,CH₂,CH₂OH.

In some embodiments, R⁴ is C₁-C₄alkyl substituted with OH or F.

In some embodiments, R^(C) is H or methyl.

In some embodiments, R⁵ is selected from the group consisting of H, F,Cl, CN, methyl, and CH(OH)CH₃.

In some embodiments, the present disclosure provides a compoundrepresented by the following structural formula (IIa):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compoundrepresented by the following structural formula (II):

or a pharmaceutically acceptable salt thereof.

In some embodiments, Ring A is C₃-C₈cycloalkyl, optionally substitutedwith 1 to 3 groups each independently selected from the group consistingof halo, OH, ═O, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, wherein the C₁-C₄alkyland C₁-C₄alkoxy are each optionally substituted with 1 to 3 groups eachindependently selected from the group consisting of halo, OH, and CN.

In some embodiments, Ring A is C₃-C₈cycloalkyl, optionally substitutedwith 1 to 3 groups each independently selected from the group consistingof D, halo, OH, ═O, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, wherein theC₁-C₄alkyl and C₁-C₄alkoxy are each optionally substituted with 1 to 3groups each independently selected from the group consisting of halo,OH, and CN.

In some embodiments, Ring A is phenyl, optionally substituted with 1 to3 groups each independently selected from the group consisting of halo,OH, ═O, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, wherein the C₁-C₄alkyl andC₁-C₄alkoxy are each optionally substituted with 1 to 3 groups eachindependently selected from the group consisting of halo, OH, and CN.

In some embodiments, Ring A is phenyl, optionally substituted with 1 to3 groups each independently selected from the group consisting of D,halo, OH, ═O, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, wherein the C₁-C₄alkyland C₁-C₄alkoxy are each optionally substituted with 1 to 3 groups eachindependently selected from the group consisting of halo, OH, and CN.

In some embodiments, Ring A is 4 to 10-membered heterocyclyl, optionallysubstituted on a ring carbon with 1 to 3 groups each independentlyselected from the group consisting of halo, OH, ═O, CN, C₁-C₄alkyl, andC₁-C₄alkoxy, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are each optionallysubstituted with 1 to 3 groups each independently selected from thegroup consisting of halo, OH, and CN.

In some embodiments, Ring A is 4 to 10-membered heterocyclyl, optionallysubstituted on a ring carbon with 1 to 3 groups each independentlyselected from the group consisting of D, halo, OH, ═O, CN, C₁-C₄alkyl,and C₁-C₄alkoxy, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are eachoptionally substituted with 1 to 3 groups each independently selectedfrom the group consisting of halo, OH, and CN.

In some embodiments, Ring A is

In some embodiments, Ring A is 4 to 10-membered heteroaryl, optionallysubstituted on a ring carbon with 1 to 3 groups each independentlyselected from the group consisting of halo, OH, ═O, CN, C₁-C₄alkyl, andC₁-C₄alkoxy, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are each optionallysubstituted with 1 to 3 groups each independently selected from thegroup consisting of halo, OH, and CN.

In some embodiments, Ring A is 4 to 10-membered heteroaryl, optionallysubstituted on a ring carbon with 1 to 3 groups each independentlyselected from the group consisting of D, halo, OH, ═O, CN, C₁-C₄alkyl,and C₁-C₄alkoxy, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are eachoptionally substituted with 1 to 3 groups each independently selectedfrom the group consisting of halo, OH, and CN.

In some embodiments, the present disclosure provides a compoundrepresented by the following structural formula (IIIa):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compoundrepresented by the following structural formula (III):

or a pharmaceutically acceptable salt thereof.

In some embodiments, Ring B is C₃-C₈cycloalkyl, optionally substitutedwith 1 to 3 groups each independently selected from the group consistingof halo, OH, ═O, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, wherein the C₁-C₄alkyland C₁-C₄alkoxy are each optionally substituted with 1 to 3 groups eachindependently selected from the group consisting of halo, OH, and CN.

In some embodiments, Ring B is C₃-C₈cycloalkyl, optionally substitutedwith 1 to 3 groups each independently selected from the group consistingof D, halo, OH, ═O, CN, C₁-C₄alkyl, and C₁-C₄alkoxy, wherein theC₁-C₄alkyl and C₁-C₄alkoxy are each optionally substituted with 1 to 3groups each independently selected from the group consisting of halo,OH, and CN.

In some embodiments, Ring B is 4 to 10-membered heterocyclyl, optionallysubstituted on a ring carbon with 1 to 3 groups each independentlyselected from the group consisting of halo, OH, ═O, CN, C₁-C₄alkyl, andC₁-C₄alkoxy, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are each optionallysubstituted with 1 to 3 groups each independently selected from thegroup consisting of halo, OH, and CN.

In some embodiments, Ring B is 4 to 10-membered heterocyclyl, optionallysubstituted on a ring carbon with 1 to 3 groups each independentlyselected from the group consisting of D, halo, OH, ═O, CN, C₁-C₄alkyl,and C₁-C₄alkoxy, wherein the C₁-C₄alkyl and C₁-C₄alkoxy are eachoptionally substituted with 1 to 3 groups each independently selectedfrom the group consisting of halo, OH, and CN.

In some embodiments, R² is selected from the group consisting of methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, andtert-butyl, each of which is optionally substituted with 1 to 4 groupseach independently selected from the group consisting of halo, OH, CN,and 5 to 6-membered heteroaryl.

In some embodiments, R² is selected from the group consisting of methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, andtert-butyl, each of which is optionally substituted with 1 to 4 groupseach independently selected from the group consisting of D, halo, OH,CN, and 5 to 6-membered heteroaryl.

In some embodiments, R³ is selected from the group consisting of H,C₁-C₄alkyl, C₃-C₈cycloalkyl, and 4 to 10-membered heterocyclyl, whereinthe C₁-C₄alkyl, C₃-C₈cycloalkyl, and 4 to 10-membered heterocyclyl areeach optionally substituted (on a ring carbon if R³ is 4 to 10-memberedheterocyclyl) with 1 to 3 groups each independently selected from haloand OH.

In some embodiments, R³ is selected from the group consisting of H, D,C₁-C₄alkyl, C₃-C₈cycloalkyl, and 4 to 10-membered heterocyclyl, whereinthe C₁-C₄alkyl, C₃-C₈cycloalkyl, and 4 to 10-membered heterocyclyl areeach optionally substituted (on a ring carbon if R³ is 4 to 10-memberedheterocyclyl) with 1 to 3 groups each independently selected from thegroup consisting of D, halo, and OH.

In some embodiments, R³ is selected from the group consisting of H,methyl, ethyl, cyclopropyl, and oxetanyl, each of which is optionallysubstituted (on a ring carbon if R³ is oxetanyl) with 1 to 3 groups eachindependently selected from halo and OH.

In some embodiments, R³ is selected from the group consisting of H, D,methyl, ethyl, cyclopropyl, and oxetanyl, each of which is optionallysubstituted (on a ring carbon if R³ is oxetanyl) with 1 to 3 groups eachindependently selected from the group consisting of D, halo, and OH.

In some embodiments, R³ is H.

In some embodiments, R³ is D.

In some embodiments, R⁴ is H or CH₃.

In some embodiments, R⁴ is selected from the group consisting of H, D,and CH₃.

In some embodiments, R⁴ is H.

In some embodiments, R⁴ is D.

In some embodiments, R⁵ is selected from the group consisting of H,halo, CN, methyl, and ethyl, wherein the methyl and ethyl are optionallysubstituted with OH.

In some embodiments, R⁵ is selected from the group consisting of H, D,halo, CN, methyl, and ethyl, wherein the methyl and ethyl are optionallysubstituted with OH.

In some embodiments, R⁵ is H.

In some embodiments, R⁵ is D.

In some embodiments, the compound is of Formula IVa-1 or IVb-1:

or

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is of Formula IVa or IVb:

or

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from a compound of FormulaVa-1, Vb-1, Vc-1, and Vd-1:

and

or a pharmaceutically acceptable salt thereof.

In some embodiments, R⁶ is H. In some embodiments, R⁶ is D.

In some embodiments, R⁷ is H. In some embodiments, R⁷ is D.

In some embodiments, the compound is selected from a compound of FormulaVa, Vb, Vc, and Vd:

and

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is a compound or a pharmaceuticallyacceptable salt thereof selected from the following table:

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Also contemplated herein is a compound represented by:

or a pharmaceutically acceptable salt thereof.

The term “pharmaceutically acceptable salt” refers to a pharmaceuticalsalt that is, within the scope of sound medical judgment, suitable foruse in contact with the tissues of humans and lower animals withoutundue toxicity, irritation, and allergic response, and is commensuratewith a reasonable benefit/risk ratio. Pharmaceutically acceptable saltsare well known in the art. For example, S. M. Berge et al. describespharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

Included in the present teachings are pharmaceutically acceptable saltsof the compounds disclosed herein. Compounds having basic groups canform pharmaceutically acceptable salts with pharmaceutically acceptableacid(s). Suitable pharmaceutically acceptable acid addition salts of thecompounds described herein include salts of inorganic acids (such ashydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, andsulfuric acids) and of organic acids (such as acetic, benzenesulfonic,benzoic, ethanesulfonic, methanesulfonic, and succinic acids). Compoundsof the present teachings with acidic groups such as carboxylic acids canform pharmaceutically acceptable salts with pharmaceutically acceptablebase(s). Suitable pharmaceutically acceptable basic salts includeammonium salts, alkali metal salts (such as sodium and potassium salts)and alkaline earth metal salts (such as magnesium and calcium salts).

Compounds having one or more chiral centers can exist in variousstereoisomeric forms, i.e., each chiral center can have an R or Sconfiguration, or can be a mixture of both. Stereoisomers are compoundsthat differ only in their spatial arrangement. Stereoisomers include alldiastereomeric and enantiomeric forms of a compound. Enantiomers arestereoisomers that are mirror images of each other. Diastereomers arestereoisomers having two or more chiral centers that are not identicaland are not mirror images of each other.

When the stereochemical configuration at a chiral center in a compoundhaving one or more chiral centers is depicted by its chemical name(e.g., where the configuration is indicated in the chemical name by “R”or “S”) or structure (e.g., the configuration is indicated by “wedge”bonds), the enrichment of the indicated configuration relative to theopposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or99.9% (except when the designation “rac” or “racemate accompanies thestructure or name, as explained in the following two paragraphs).“Enrichment of the indicated configuration relative to the oppositeconfiguration” is a mole percent and is determined by dividing thenumber of compounds with the indicated stereochemical configuration atthe chiral center(s) by the total number of all of the compounds withthe same or opposite stereochemical configuration in a mixture.

When the stereochemical configuration at a chiral center in a compoundis depicted by chemical name (e.g., where the configuration is indicatedin the name by “R” or “S”) or structure (e.g., the configuration isindicated by “wedge” bonds) and the designation “rac” or “racemate”accompanies the structure or is designated in the chemical name, aracemic mixture is intended.

When two stereoisomers are depicted by their chemical names orstructures, and the names or structures are connected by an “or”, one orthe other of the two stereoisomers is intended, but not both.

When a disclosed compound having a chiral center is depicted by astructure without showing a configuration at that chiral center, thestructure is meant to encompass the compound with the S configuration atthat chiral center, the compound with the R configuration at that chiralcenter, or the compound with a mixture of the R and S configuration atthat chiral center. When a disclosed compound having a chiral center isdepicted by its chemical name without indicating a configuration at thatchiral center with “S” or “R”, the name is meant to encompass thecompound with the S configuration at that chiral center, the compoundwith the R configuration at that chiral center or the compound with amixture of the R and S configuration at that chiral center.

A racemic mixture means a mixture of 50% of one enantiomer and 50% ofits corresponding enantiomer. The present teachings encompass allenantiomerically-pure, enantiomerically-enriched, diastereomericallypure, diastereomerically enriched, and racemic mixtures, anddiastereomeric mixtures of the compounds disclosed herein.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

“Peak 1” in the Experimental section refers to an intended reactionproduct compound obtained from a chromatography separation/purificationthat elutes earlier than a second intended reaction product compoundfrom the same preceding reaction. The second intended product compoundis referred to as “peak 2”.

When a disclosed compound is designated by a name or structure thatindicates a single enantiomer, unless indicated otherwise, the compoundis at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (alsoreferred to as “enantiomerically pure”). Optical purity is the weight inthe mixture of the named or depicted enantiomer divided by the totalweight in the mixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat, unless otherwise indicated, one of the encompassed stereoisomersor any mixture of the encompassed stereoisomers are included. It is tobe further understood that the stereoisomeric purity of the named ordepicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% byweight. The stereoisomeric purity in this case is determined by dividingthe total weight in the mixture of the stereoisomers encompassed by thename or structure by the total weight in the mixture of all of thestereoisomers.

In the compounds of the disclosure, any position specifically designatedas “D” or “deuterium” is understood to have deuterium enrichment at 50,80, 90, 95, 98 or 99%. “Deuterium enrichment” is a mole percent and isdetermined by dividing the number of compounds with deuterium at theindicated position by the total number of all of the compounds. When aposition is designated as “H” or “hydrogen”, the position has hydrogenat its natural abundance. When a position is silent as to whetherhydrogen or deuterium is present, the position has hydrogen at itsnatural abundance. One specific alternative embodiment is directed to acompound of the disclosure having deuterium enrichment of at least 5,10, 25, 50, 80, 90, 95, 98 or 99% at one or more positions notspecifically designated as “D” or “deuterium”.

As used herein, many moieties (e.g., alkyl, alkoxy, cycloalkyl orheterocyclyl) are referred to as being either “substituted” or“optionally substituted”. When a moiety is modified by one of theseterms, unless otherwise noted, it denotes that any portion of the moietythat is known to one skilled in the art as being available forsubstitution can be substituted, which includes one or moresubstituents. Where if more than one substituent is present, then eachsubstituent may be independently selected. Such means for substitutionare well-known in the art and/or taught by the instant disclosure. Theoptional substituents can be any substituents that are suitable toattach to the moiety.

Compounds of the disclosure are CDK2 inhibitors. As used herein, theterm “selective CDK2 inhibitor” means a compound which selectivelyinhibits CDK2 over other CDKs and the kinome. Said another way, aselective CDK2 inhibitor has no or low activity against other CDKs andthe kinome. A selective CDK2 inhibitor’s inhibitory activity againstCDK2 is more potent in terms of IC₅₀ value (i.e., the IC₅₀ value issubnanomolar) when compared with its inhibitory activity against otherCDKs and many other kinases. Potency can be measured using knownbiochemical assays.

In some embodiments, the compounds of the disclosure are selectiveagainst CDK2 versus CDK1. In some such embodiments, compounds show atleast 10-fold selectivity for CDK2 versus CDK1. In other embodiments,compounds show at least 20-fold selectivity for CDK2 versus CDK1. Inspecific embodiments, compounds show at least 30-fold selectivity forCDK2 versus CDK1. In certain embodiments, compounds show at least40-fold selectivity for CDK2 versus CDK1. In other embodiments,compounds show at least 50-fold selectivity for CDK2 versus CDK1. Forexample, compounds show at least 100-fold selectivity for CDK2 versusCDK1.In some embodiments, the compounds of the invention are selectiveagainst CDK2 versus CDK4 and/or CDK6. In some such embodiments,compounds show at least 10-fold selectivity for CDK2 versus CDK4 and/orCDK6. In other embodiments, compounds show at least 20-fold selectivityfor CDK2 versus CDK4 and/or CDK6. In specific embodiments, compoundsshow at least 30-fold selectivity for CDK2 versus CDK4 and/or CDK6.

Some compounds of the disclosure have the advantage of good metabolicstability. One indicator of good metabolic stability is high microsomalstability. Hepatic metabolism is a predominant route of elimination forsmall molecule drugs. The clearance of compounds by hepatic metabolismcan be assessed in vitro using human liver microsomes (HLMs) or humanhepatocytes. Compounds are incubated with HLMs plus appropriatecofactors or human hepatocytes and compound depletion is measured todetermine an in vitro intrinsic clearance (Clint). The Clint is scaledto total body clearance (CL), and a hepatic extraction ratio (ER) isdetermined by dividing CL to standard human hepatic blood flow.Compounds that have a low hepatic extraction ratio are considered tohave good metabolic stability. In some embodiments, a compound of thedisclosure has a calculated ER of <0.3, <0.4, <0.5, <0.6.

Pharmaceutical Compositions

Pharmaceutical compositions of the disclosure (also referred to hereinas the “disclosed pharmaceutical compositions”) comprise one or morepharmaceutically acceptable carrier(s) or diluent(s) and a compound ofthe disclosure (e.g., a compound of Formula (I) or Formula (Ia)), or apharmaceutically acceptable salt thereof.

“Pharmaceutically acceptable carrier” and “pharmaceutically acceptablediluent” refer to a substance that aids the formulation and/oradministration of an active agent to and/or absorption by a subject andcan be included in the pharmaceutical compositions of the disclosurewithout causing a significant adverse toxicological effect on thesubject. Nonlimiting examples of pharmaceutically acceptable carriersand/or diluents include water, NaCl, normal saline solutions, lactatedRinger’s, normal sucrose, normal glucose, binders, fillers,disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions(such as Ringer’s solution), alcohols, oils, gelatins, carbohydratessuch as lactose, amylose or starch, hydroxymethycellulose, fatty acidesters, polyvinyl pyrrolidine, and colors, and the like. Suchpreparations can be sterilized and, if desired, mixed with auxiliaryagents such as lubricants, preservatives, stabilizers, wetting agents,emulsifiers, salts for influencing osmotic pressure, buffers, coloring,and/or aromatic substances and the like that do not deleteriously reactwith or interfere with the activity of the compounds provided herein.One of ordinary skill in the art will recognize that otherpharmaceutical excipients are suitable for use with disclosed compoundsor pharmaceutically acceptable salts thereof.

The pharmaceutical compositions of the disclosure optionally include oneor more pharmaceutically acceptable carriers and/or diluents therefor,such as lactose, starch, cellulose and dextrose. Other excipients, suchas flavoring agents, sweeteners, and preservatives, such as methyl,ethyl, propyl and butyl parabens, can also be included. More completelistings of suitable excipients can be found in the Handbook ofPharmaceutical Excipients (5^(th) Ed., Pharmaceutical Press (2005)). Aperson skilled in the art would know how to prepare formulationssuitable for various types of administration routes. Conventionalprocedures and ingredients for the selection and preparation of suitableformulations are described, for example, in Remington’s PharmaceuticalSciences (2003 -20th edition) and in The United States Pharmacopeia: TheNational Formulary (USP 24 NF19) published in 1999. The carriers,diluents and/or excipients are “acceptable” in the sense of beingcompatible with the other ingredients of the pharmaceutical compositionand not deleterious to the recipient thereof.

Methods of Treatment

The compounds disclosed herein inhibit CDK2 and therefore are useful fortreating diseases for which CDK2 is dysregulated, such as cancer. Thepresent disclosure provides a method of inhibiting CDK2 in a subject inneed thereof, comprising administering to the subject an effectiveamount of a compound disclosed herein, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition disclosed herein.

In some embodiments, the disclosure provides a method of treating adisease or disorder associated with CDK2 in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I) or Formula (Ia) or any of the formulas asdescribed herein, or a pharmaceutically acceptable salt thereof. In someembodiments, the disease or disorder associated with CDK2 is associatedwith an amplification of the cyclin E1 (CCNE1) gene and/oroverexpression of CCNE1. In some embodiments, the disease or disorder iscancer.

Subjects “in need of inhibiting CDK2” are those having a disease forwhich a beneficial therapeutic effect can be achieved by inhibitingCDK2, e.g., a slowing in disease progression, alleviation of one or moresymptoms associated with the disease or increasing the longevity of thesubject in view of the disease.

In some embodiments, the disclosure provides a method of treating adisease/condition/or cancer associated with or modulated by CDK2,wherein the inhibition of CDK2 is of therapeutic benefit, including butnot limited to the treatment of cancer in a subject in need thereof. Themethod comprises administering to the subject an effective amount of acompound disclosed herein, a pharmaceutically acceptable salt thereof,or pharmaceutical composition disclosed herein.

In another embodiment, the disclosure provides a method of treating asubject with cancer, comprising administering to the subject aneffective amount of a compound disclosed herein, a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition disclosedherein. In another embodiment, the cancer is characterized byamplification and/or overexpression of CCNE1 or CCNE2.

Accordingly, in some embodiments of the methods, the subject or patienthas been previously determined to have an amplification of the cyclin E1(CCNE1) gene and/or an expression level of CCNE1 in a biological sampleobtained from the subject or patient that is higher than a controlexpression level of CCNE1.

In another embodiment, the disclosure provides a method for inhibitinggrowth of tumor (e.g., cancer) cells in vitro. The method includescontacting the tumor (e.g. cancer) cells in vitro with a compound ofFormula (1) or Formula (Ia) or a pharmaceutically acceptable saltthereof. In another embodiment, the present disclosure provides a methodfor inhibiting growth of tumor (e.g., cancer) cells with CCNE1amplification and/or overexpression in a subject or a patient. Themethod includes administering to the subject or patient in need thereofa therapeutically effective amount of a compound of Formula (I) orFormula (Ia), or a pharmaceutically acceptable salt thereof.

In another embodiment, the disclosure provides a method of treating asubject with cancer, comprising administering to the subject aneffective amount of a compound disclosed herein, a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition disclosedherein in conjunction with other agents or standard cancer treatments,as described below.

As used herein “cancer” refers to any malignant and/or invasive growthor tumor caused by abnormal cell growth. Cancer includes solid tumorsnamed for the type of cells that form them, cancer of blood, bonemarrow, or the lymphatic system. Examples of solid tumors includesarcomas and carcinomas. Cancers of the blood include, but are notlimited to, leukemia, lymphoma and myeloma. Cancer also includes primarycancer that originates at a specific site in the body, a metastaticcancer that has spread from the place in which it started to other partsof the body, a recurrence from the original primary cancer afterremission, and a second primary cancer that is a new primary cancer in aperson with a history of previous cancer of a different type from thelatter one. In some such embodiments, the cancer is characterized byamplification and/or overexpression of CCNE1 and/or CCNE2.

Cancers to be treated according to the disclosed methods include breastcancer, ovarian cancer, bladder cancer, uterine cancer (e.g., uterinecarcinosarcoma), prostate cancer, lung cancer (including NSCLC, SCLC,squamous cell carcinoma (e.g., lung squamous cell carcinoma (LUSC), oradenocarcinoma (e.g., lung adenocarcinoma (LUAD)), esophageal cancer,head and neck cancer, colorectal cancer (e.g., colon cancer, colorectaladenocarcinoma (COADREAD)), kidney cancer (including RCC), liver cancer(including HCC), pancreatic cancer, stomach (i.e., gastric) cancer,urothelial cancer, brain cancers, mesothelioma (MESO), skin cancer(e.g., melanoma), sarcoma, or thyroid cancer, including metastasis (inparticular brain metastasis) of all cancers listed. In some embodiments,the cancer is characterized by at overexpression and/or amplification ofCCNE1 and/or CCNE2 described herein. In some embodiments of the methodsprovided herein, the subject is identified as having a cancercharacterized by amplification and/or overexpression of CCNE1 and/orCCNE2.

In further embodiments of the methods provided herein, the cancer isbreast cancer, ovarian cancer, bladder cancer, uterine cancer, prostatecancer, lung cancer, esophageal cancer, liver cancer, pancreatic canceror stomach cancer. In some such embodiments, the cancer is characterizedby amplification and/or overexpression of CCNE1 and/or CCNE2.

In further embodiments, of the methods provided herein, the cancer isselected from the group consisting of ovarian cancer, endometrialcancer, gastric cancer, esophageal cancer, triple negative breastcancer, and lung adenosarcoma. In some embodiments, the cancer ischaracterized by CCNE1 overexpression and/or amplification. In someembodiments, the cancer has progressed despite platinum treatment.

In some embodiments, the cancer is platinum-resistant and/orplatinum-refractory. In some embodiments, the cancer has progresseddespite platinum treatment.

In some embodiments, the disease or disorder associated with CDK2 is anadenocarcinoma, carcinoma, or cystadenocarcinoma.

In other embodiments, the cancer is breast cancer, including, e.g.,ER-positive/HR-positive, HER2-negative breast cancer;ER-positive/HR-positive, HER2-positive breast cancer; triple negativebreast cancer (TNBC); or inflammatory breast cancer. In someembodiments, the breast cancer is chemotherapy or radiotherapy resistantbreast cancer, endocrine resistant breast cancer, trastuzumab resistantbreast cancer, or breast cancer demonstrating primary or acquiredresistance to CDK4/CDK6 inhibition. In some embodiments, the breastcancer is advanced or metastatic breast cancer. In some embodiments ofeach of the foregoing, the breast cancer is characterized byamplification and/or overexpression of CCNE1 and/or CCNE2.

In some embodiments, the cancer is HR-positive breast cancer. In someembodiments, the breast cancer is ER-positive breast cancer. In someembodiments, the breast cancer is HR-positive, HER2-negative breastcancer. In some embodiments, the breast cancer is ER-positive,HER2-negative breast cancer. In some embodiments, the breast cancer isresponsive to treatment with a CDK4/6 inhibitor. In some embodiments,the breast cancer is resistant to treatment with a CDK4/6 inhibitor. Insome embodiments, the breast cancer has progressed despite treatmentwith a CDK4/6 inhibitor. In some embodiments, the CDK4/6 inhibitor ispalbociclib. In some embodiments, the breast cancer has progresseddespite first treatment with palbociclib and/or fulvestrant and secondtreatment with abemaciclib and/or fulvestrant. In some embodiments, themethod further comprises administering an effective amount of a CDK4/6inhibitor. In some embodiments, the CDK4/6 inhibitor is selected frompalbociclib and ribociclib, or a combination thereof. In someembodiments, the CDK4/6 inhibitor is ribociclib. In some embodiments,the breast cancer has CCNE amplification and/or overexpression.

In some embodiments, the breast cancer is triple negative breast cancer.

In some embodiments, the cancer is ovarian cancer. In some suchembodiments, the cancer is ovarian cancer characterized by amplificationand/or overexpression of CCNE1 and/or CCNE2. In some such embodiments,the cancer is (a) ovarian cancer; (b) characterized by amplificationand/or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c)both (a) and (b). In some embodiments, the cancer is ovarian cancer.

In some embodiments, the compound of the disclosure is administered asfirst line therapy. In other embodiments, the compound of the disclosureis administered as second (or later) line therapy. In some embodiments,the compound of the disclosure is administered as second (or later) linetherapy following treatment with an endocrine therapeutic agent and/or aCDK4/CDK6 inhibitor. In some embodiments, the compound of the disclosureis administered as second (or later) line therapy following treatmentwith an endocrine therapeutic agent, e.g., an aromatase inhibitor, aSERM or a SERD. In some embodiments, the compound of the disclosure isadministered as second (or later) line therapy following treatment witha CDK4/CDK6 inhibitor. In some embodiments, the compound of thedisclosure is administered as second (or later) line therapy followingtreatment with one or more chemotherapy regimens, e.g., includingtaxanes or platinum agents. In some embodiments, the compound of thedisclosure is administered as second (or later) line therapy followingtreatment with HER2 targeted agents, e.g., trastuzumab.

In some embodiments, the disease or disorder associated with CDK2 isN-myc amplified neuroblastoma cells (see Molenaar, et al., Proc NatlAcad Sci USA 106(31): 12968-12973) K-Ras mutant lung cancers (see Hu,S., et al., Mol Cancer Ther, 2015. 14(11): 2576-85, and cancers withFBW7 mutation and CCNE1 overexpression (see Takada, et al., Cancer Res,2017.77(18): 4881-4893).

In some embodiments, the compounds of the present disclosure can be usedto treat sickle cell disease and sickle cell anemia.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin’s Disease, non-Hodgkin’slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi’ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include, but are not limited to, melanoma (e.g., metastaticmalignant melanoma, BRAF and HSP90 inhibition-resistant melanoma, skincutaneous melanoma (SKCM), renal cancer (e.g., clear cell carcinoma),prostate cancer (e.g., hormone refractory prostate adenocarcinoma),breast cancer, colon cancer, lung cancer (e.g., non-small cell lungcancer and small cell lung cancer), squamous cell head and neck cancer(e.g., head and neck squamous cell carcinoma (NHSC), urothelial cancer(e.g., bladder) and cancers with high microsatellite instability(MSIhigh). Additionally, the disclosure includes refractory or recurrentmalignancies whose growth may be inhibited using the compounds of thedisclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including follicularlymphoma, including relapsed or refractory NHL and recurrentfollicular), Hodgkin lymphoma or multiple myeloma) and combinations ofsaid cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to,cholangiocarcinoma, bile duct cancer, triple negative breast cancer,rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellularcarcinoma (e.g., liver hepatocellular carcinoma (LIHC)), Ewing’ssarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma,neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma,eye cancer, Fallopian tube cancer, gastrointestinal cancer,gastrointestinal stromal tumors, hairy cell leukemia, intestinal cancer,islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngealcancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer,ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cellcarcinoma, salivary gland cancer, sinus cancer, spinal cancer, tonguecancer, tubular carcinoma, urethral cancer, and ureteral cancer.

In some embodiments, cancers treatable with compounds of the presentdisclosure include Genomic Identification of Significant Targets inCancer (GISTIC) and pheochromocytoma and paraganglioma (PCPG).

In some embodiments, cancers treatable with compounds of the presentdisclosure include advanced/relapsed tumors; CCNE1 amplifiedplatinum-resistant or platinum-refractory ovarian cancer; endometrialcancer (with prior platinum therapy) that has progressed following 2 ormore lines of therapies; and gastric cancer (with prior platinumtherapy) that has progressed following 2 or more lines of therapies; andER+ HER2.. BC that has progressed despite CDK4/6i. In some embodiments,cancers treatable with compounds of the present disclosure includePlatinum-resistant or platinum-refractory CCNE1 amplified ovariancancer; CCNE1 amplified endometrial cancer that has failed 2 or morelines of therapies; CCNE1 amplified advanced/relapsed tumors that do notbelong to the other groups; ER+ HER2- BC that has progressed despiteCDK4/6i; platinum-resistant or platinum-refractory CCNE1 amplifiedovarian cancer; and ER+ HER2- BC that has progressed despite CDK4/6i.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), and essential thrombocytosis (ET)),myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma(T-ALL) and multiple myeloma (MM).

Exemplary sarcomas include chondrosarcoma, Ewing’s sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, hannatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer (SCLC), bronchogenic carcinoma, squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma. Exemplary gastrointestinalcancers include cancers of the esophagus (squamous cell carcinoma,adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm’s tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma (PRAD), sarcoma), and testis (seminoma,teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma,sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoidtumors, lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing’s sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,medulloblastoma, glioma, brain lower grade glioma (LGG), ependymoma,germinoma (pinealoma), glioblastoma, glioblastoma multiforme (GBM),oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, andspinal cord (neurofibroma, meningioma, glioma, sarcoma), as well asneuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, cervical squamouscell carcinoma (CESC), pre -tumor cervical dysplasia), ovaries (ovariancarcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma,unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydigcell tumors, dysgerminoma, malignant teratoma), vulva (squamous cellcarcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma,melanoma), vagina (clear cell carcinoma, squamous cell carcinoma,botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes(carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, Merkelcell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

Combinations

Compounds of the disclosure may be administered as single agents or maybe administered in combination with other anti-cancer therapeuticagents, in particular standard of care agents appropriate for theparticular cancer.

The term “additional anticancer therapeutic agent” as used herein meansany one or more therapeutic agent, other than a compound of thedisclosure, that is or can be used in the treatment of cancer. In someembodiments, such additional anticancer therapeutic agents includecompounds derived from the following classes: mitotic inhibitors,alkylating agents, antimetabolites, antitumor antibiotics,anti-angiogenesis agents, topoisomerase I and II inhibitors, plantalkaloids, hormonal agents and antagonists, growth factor inhibitors,radiation, signal transduction inhibitors, such as inhibitors of proteintyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors,biological response modifiers, enzyme inhibitors, antisenseoligonucleotides or oligonucleotide derivatives, cytotoxics,immunooncology agents, and the like.

In some embodiments, the additional anticancer agent is an endocrineagent, such as an aromatase inhibitor, a SERD or a SERM.

In some embodiments, the additional anticancer agent is a PIK3CAinhibitor including, but not limited to, alpelisib (PIQRAY), BEBT-908,BPI-21668, buparlisib, inavolisib, TQB-3525, RLY-2608, miransertib,MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatolisib, and fimepinostat.

In some embodiments, the additional anticancer agent is an antibody-drugconjugates including, but not limited to, Trastuzumab deruxtecan(Enhertu), Trastuzumab duocarmazine, Trastuzumab emtansine (Kadcyla),Upifitarnab rilsodotin, mirvetuximab soravtansine, Tisotumab vedotin(Tivdak), Praluzatamab ravtansine, Sacituzumab govitecan or SacituzumabGovitecan-hziy (Trodelvy), Datopotamab deruxtecan, Ladiratuzumabvedotin, Patritumab deruxtecan, STRO-002, MORab-202, DS-6000, Anetumab,avtansine, XMT-2056, Disitamab Vedotin (RC48-ADC, Aidexi).

In some embodiments, the additional anticancer agent is a PLK1 inhibitorincluding, but not limited to onvansertib, BI2536, BI6727, GSK461364A,TAK960, rigosertib.

In some embodiments, the additional anticancer agent is Estrogen PROTAC(ARV-471, H3B-5942).

In other embodiments, a compound of the disclosure may be administeredin combination with a standard of care agent. In some embodiments, acompound of the disclosure may be administered in combination withendocrine therapy, e.g., agents such as letrozole, fulvestrant,tamoxifen, exemestane, or anastrozole. In some embodiments, a compoundof the disclosure may be administered in combination with achemotherapeutic agent, e.g., docetaxel, paclitaxel, cisplatin,carboplatin, capecitabine, gemcitabine, vinorelbine, or liposomaldoxorubicin. In other embodiments, a compound of the invention may beadministered in combination with an anti-HER2 agent, e.g., trastuzumabor pertuirmnab.

In some embodiments, a compound of the disclosure (for example, acompound of Formula (I), Formula (Ia), Formula (II), Formula (IIa),Formula (III), Formula (IIIa), Formula (IVa), Formula (IVb), Formula(IVa-1), Formula (IVb-1), Formula (Va), Formula (Vb), Formula (Vc),Formula (Vd), Formula (Va-1), Formula (Vb-1), Formula (Vc-1), or Formula(Vd-1) or a pharmaceutically acceptable salt thereof may be administeredin combination with an effective amount of carboplatin, ribociclib,fulvestrant, or a combination thereof.

In some embodiments, the additional anticancer agent is ananti-angiogenesis agent, including for example VEGF inhibitors, VEGFRinhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors,PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins(alpha-v/beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, andMMP-9 (matrix-metalloproteinase 9) inhibitors. Preferredanti-angiogenesis agents include sunitinib (Sutent™), bevacizumab(Avastin™), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958(Pfizer). Additional anti-angiogenesis agents include vatalanib (CGP79787), Sorafenib (Nexavar™), pegaptanib octasodium (Marugen™),vandetanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171(AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941),tetrathiomolybdata (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005),CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352),and CP-868,596 (Pfizer). Other anti-angiogenesis agents includeenzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401),teprenone (Selbex™) and UCN 01 (Kyowa Hakko). Other examples ofanti-angiogenesis agents include celecoxib (Celebrex™), parecoxib(Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib(Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus),SC-58125 (Pharmacia) and etoricoxib (Arcoxia™). Yet furtheranti-angiogenesis agents include exisulind (Aptosyn™), salsalate(Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen(Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen(Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™),sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™),ketorolac (Toradol™), and oxaprozin (Daypro™). Yet furtheranti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005).AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon).

Yet further anti-angiogenesis agents (including VEGFR / PDGFRinhibitors) include, but are not limited to, ponatinib (Iclusig),BT1718, anlotinib, lenvatinib (Lenvima), tivozanib (Fotivda), dovitinib,brolucizumab (Beovu), aflibercept (Eylea), and faricimab.

Yet further anti-angiogenesis agents include acitretin (Neotigason™),plitidepsin (aplidine™), cilengtide (EMD 121974), combretastatin A4(CA4P), fenretinide (4 HPR), halofuginone (Tempostatin™), Panzem™(2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291),catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™),thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MEDI 522), andzoledronic acid (Zometa™).

In other embodiments, the additional anti-cancer agent is a so-calledsignal transduction inhibitor (e.g., inhibiting how regulatory moleculesthat govern the fundamental processes of cell growth, differentiation,and survival communicated within the cell). Signal transductioninhibitors include small molecules, antibodies, and antisense molecules.Signal transduction inhibitors include for example kinase inhibitors(e.g., tyrosine kinase inhibitors or serine/threonine kinase inhibitors)and cell cycle inhibitors. More specifically signal transductioninhibitors include, for example, farnesyl protein transferaseinhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, IGFIRinhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors,PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinaseinhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors,inhibitors of the WNT pathway and so called multi-targeted kinaseinhibitors. Additional examples of signal transduction inhibitors whichmay be used in conjunction with a compound of the invention andpharmaceutical compositions described herein include BMS 214662(Bristol-Myers Squibb), lonafarnib (Sarasar™), pelitrexol (AG 2037),matuzumab (EMD 7200), nimotuzumab (TheraCIM h-R3™), panitumumab(Vectibix™), Vandetanib (Zactima™), pazopanib (SB 786034), ALT 110(Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim),and Cervene™(TP 38). Other examples of signal transduction inhibitors includegefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™),trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™),crizotinib (Pfizer), lorlatinib (Pfizer), dacomitinib (Pfizer),bosutinib (Pfizer), gedatolisib (Pfizer), canertinib (CI 1033),pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB 569),miltefosine (Miltefosin™), BMS 599626 (Bristol-Myers Squibb),Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM 1),mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY142886 (Array Biopharm), everolimus (Certican™), zotarolimus(Endeavor™), temsirolimus (Torisel™), AP 23573 (ARIAD), and VX 680(Vertex), XL 647 (Exelixis), sorafenib (Nexavar™), LE-AON (GeorgetownUniversity), and GI-4000 (Globelmmune). Other signal transductioninhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib(CYC 200), BIO 112 (Onc Bio), BMS 387032 (Bristol-Myers Squibb),palbociclib (Pfizer), and AG 024322 (Pfizer).

In other embodiments, the additional anti-cancer agent is a so calledclassical antineoplastic agent. Classical antineoplastic agents includebut are not limited to hormonal modulators such as hormonal,anti-hormonal, androgen agonist, androgen antagonist and anti-estrogentherapeutic agents, histone deacetylase (HDAC) inhibitors, DNAmethyltransferase inhibitors, silencing agents or gene activatingagents, ribonucleases, proteosomics, Topoisomerase I inhibitors,Camptothecin derivatives, Topoisomerase II inhibitors, alkylatingagents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1)inhibitor (such as, e.g., talazoparib, olapariv, rucaparib, niraparib,iniparib, veliparib), microtubulin inhibitors, antibiotics, plantderived spindle inhibitors, platinum-coordinated compounds, genetherapeutic agents, antisense oligonucleotides, vascular targetingagents (VTAs), and statins. Examples of classical antineoplastic agentsused in combination therapy with a compound of the invention, optionallywith one or more other agents include, but are not limited to,glucocorticoids, such as dexamethasone, prednisone, prednisolone,methylprednisolone, hydrocortisone, and progestins such asmedroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486),Selective Estrogen Receptor Modulators (SERMs; such as tamoxifen,raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene,fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene,trilostane and CHF 4227 (Cheisi), Selective Estrogen-ReceptorDownregulators (SERD’s; such as fulvestrant, LSZ102, G1T48, RAD1901,elacestrant, GDC-9545, giredestrant, SAR439859, amcenestrant, AZD9833,camizestrant, LY3484356, Zn-c5, D-0502), exeinestane (Aromasin),anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara),formestane; gonadotropin-releasing hormone (GnRH; also commonly referredto as luteinizing hormone-releasing hormone [LHRH]) agonists such asbuserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), andtriptorelin (Trelstar), abarelix (Plenaxis), cyproterone, flutamide(Eulexin), megestrol, nilutamide (Nilandron), and osaterone,dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801,abarelix, goserelin, leuprorelin, triptorelin, bicalutamide;antiandrogen agents, such as enzalutamide, abiraterone acetate,bicalutamide (Casodex); and combinations thereof. Other examples ofclassical antineoplastic agents used in combination with a compound ofthe invention include but are not limited to suberolanilide hydroxamicacid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 orFK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101;Onconase (ranpirnase),PS-341 (MLN-341), Velcade (bortezomib),9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin,diflomotecan, edotecarin, exatecan (Daiichi), gimatecan,10-hydroxycamptothecin, irinotecan HCl (Camptosar), lurtotecan,Orathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin,10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38,edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin,annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin,etoposide, idarubicin, galarubicin, hydroxy carbamide, nemorubicin,novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine,rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard(dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473,altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan,carboquone, carmustine, chlorambucil, dacarbazine, estramustine,fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide,mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C,mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, andplatinum-coordinated alkylating compounds such as cisplatin, Paraplatin(carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin(oxaliplatin, Sanofi), streptozocin, satrplatin, and combinationsthereof.

In still other embodiments, the additional anti-cancer agent is a socalled dihydrofolate reductase inhibitors (such as methotrexate andNeuTrexin (trimetresate glucuronate)), purine antagonists (such as6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine,clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed),pyrimidine antagonists (such as 5-fluorouracil (5-FU), Alimta(premetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosinearabinoside, Gemzar™ (gemcitabine, Eli Lilly), Tegafur (UFT Orzel orUforal and including TS-1 combination of tegafur, gimestat and otostat),doxifluridine, carmofur, cytarabine (including ocfosfate, phosphatestearate, sustained release and liposomal forms), enocitabine,5-azacitidine (Vidaza), decitabine, and ethynylcytidine) and otherantimetabolites such as eflornithine, hydroxyurea, leucovorin,nolatrexed (Thymitaq), triapine, trimetrexate,N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-100′1(Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals) and GPI 18180(Guilford Pharm Inc) and combinations thereof.

Other examples of classical antineoplastic cytotoxic agents include, butare not limited to, Abraxane (Abraxis BioScience, Inc.), Batabulin(Amgen), EPO 906 (Novartis), Vinflunine (Bristol- Myers Squibb Company),actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin),vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel(Taxotere), Ortataxel, paclitaxel (including Taxoprexin a DHA/paciltaxelconjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin),Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin),Taxotere alitretinoin, Canfosfamide (Telcyta™), DMXAA (Antisoma),ibandronic acid, L-asparaginase, pegaspargase (Oncaspar™), Efaproxiral(Efaproxyn™ - radiation therapy), bexarotene (Targretin™), Tesmilifene(DPPE- enhances efficacy of cytotoxics), Theratope™ (Biomira), Tretinoin(Vesanoid™), tirapazamine (Trizaone™), motexafin gadolinium (Xcytrin™)Cotara™ (mAb), and NBI-3001 (Protox Therapeutics),polyglutamate-paclitaxel (Xyotax™) and combinations thereof. Furtherexamples of classical antineoplastic agents include, but are not limitedto, as Advexin (ING 201), TNFerade (GeneVec, a compound which expressTNFalpha in response to radiotherapy), RB94 (Baylor College ofMedicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P),Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, PfizerInc.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin(Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin(Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor,AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet,Lipitor, torcetrapib, and combinations thereof.

In other embodiments, the additional anti-cancer agent is an epigeneticmodulator, for example an inhibitor or EZH2, SMARCA4, PBRM1, ARID1A,ARID2, ARID1B, DNMT3A, TET2, MLL1/2/3, NSD1/2, SETD2, BRD4, DOT1L,HKMTsanti, PRMT1-9, LSD1, UTX, ID1/2 or BCL6.

In further embodiments, the additional anti-cancer agent is animmunomodulatory agent, such as, but not limited to, an inhibitor ofCTLA-4 (e.g., ipilimumab), PD-1 or PD-L1 (e.g., pembrolizumab,nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, ordosterlimab), LAG-3 (e.g., relatlimab, TIM-3, TIGIT, 4-1BB, OX40, GITR,CD40, or a CAR-T-cell therapy.

In some embodiments, the additional anticancer agent is an EGFRinhibitor such as afatinib, osimertinib, lapatinib, erlotinib,dacomitinib, poziotinib, neratinib or gefitinib or an EGFR antibody suchas cetuximab, panitumumab, or necitumumab.

Alternatively, a compound of the disclosure, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition disclosed hereincan be administered in combination with other anti-cancer agents thatare not EGFR inhibitors e.g., in combination with MEK, including mutantMEK inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib,refametinib); c-MET, including mutant c-Met inhibitors (savolitinib,cabozantinib, foretinib) and MET antibodies (emibetuzumab); mitotickinase inhibitors (CDK4/6 inhibitors such as palbociclib, ribociclib,abemacicilb, lerociclib, trilaciclib, dalpiciclib, BPI-16350);anti-angiogenic agents e.g., bevacizumab, nintedanib; apoptosis inducerssuch as Bcl-2 inhibitors e.g, venetoclax, obatoclax, navitoclax andMcl-1 inhibitors e.g., AZD-5991, AMG-176, S-64315; and mTOR inhibitorse.g, rapamycin, temsirolimus, everolimus, ridoforolimus.

A compound of the disclosure, a pharmaceutically acceptable salt thereofor a pharmaceutical composition disclosed herein can also beadministered in combination with an effective amount of a second agentselected from the group consisting of palbociclib (e.g., ibrance®),ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g.,lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine,megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g.,xeloda®), regorafenib (e.g., stivarga®), afatinib (e.g., gilotrif®),osimertinib (e.g., tagrisso®), gefitinib (e.g., iressa®), erlotinib(e.g., tarceva®), ramucirumab (e.g., cyramza®), an EGFR inhibitor,pralsetinib, ABT-263 (navitoclax), MK-1775 (adavosertib), BAY-1895344,berzosertib, ceralasertib, SRA-737, LY2603618 (rabusertib), andtrastuzumab (e.g., herceptin®), or combinations thereof. The EGFRinhibitor may be selected from afatinib, osimertinib, lapatinib,erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02,alflutinib (AST 2818), aumolertinib (formerly almonertinib) (HS10296),BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilitertinib,icotinib, JND-3229, lazertinib, nazartinib (EGF 816), avitinib,PCC-0208027, rezivertinib (BPI-7711), TQB3804, zorifertinib (AZ-3759),or DZD9008; an EGFR antibody such as cetuximab, panitumumab,necitumumab, HLX07, JMT101; or a bispecific EGFR and MET antibody (e.g.,amivantamab ((JNJ-61186372, JNJ-372)).

Biomarkers and Pharmacodynamics Markers

The disclosure further provides predictive markers (e.g., biomarkers andpharmacodynamic markers, e.g., gene copy number, gene sequence,expression levels, or phosphorylation levels) to identify those humansubjects having, suspected of having, or at risk of developing a diseaseor disorder associated with CDK2 for whom administering a CDK2 inhibitor(“a CDK2 inhibitor” as used herein refers to a compound of thedisclosure, or a pharmaceutically acceptable salt thereof) is likely tobe effective.

Ccne1

In one embodiment, the biomarker is CCNE1. In particular anamplification of the cyclin E1 (CCNE1) gene and/or an expression levelof CCNE1 in a biological sample would indicate that the patient orsubject could benefit from administration of a compound of Formula (I)or Formula (Ia) or a pharmaceutically acceptable salt thereof.

CCNE1 is a cell cycle factor essential for the control of the cell cycleat the G1/S transition (Ohtsubo et al., 1995, Mol. Cell.Biol.15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2,interacting with CDK2 to form a serine/threonine kinase holoenzymecomplex. The CCNE1 subunit of this holoenzyme complex provides thesubstrate specificity of the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1 is encoded by the cyclin E1 (“CCNE1”) gene (GenBankAccession No. NM_001238). The amino acid sequence of human CCNE1 isfound at GenBank Accession No. NP_001229 / UniProtKB Accession No.P24864).

In one aspect, the present disclosure provides a method of treating asubject having, or at risk of developing, a disease or disorderassociated with CDK2, comprising administering to the subject atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition disclosed herein, wherein the subject has an amplificationof the CCNE1 gene and/or have an expression level of CCNE1 higher than acontrol expression level of CCNE1. In some embodiments, the disease ordisorder associated with CDK2 is cancer.

Also provided herein is a method of treating a patient having anamplified expression level of CCNE1 and suffering from, or at risk ofdeveloping, a solid tumor cancer, comprising administering to thepatient a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition disclosed herein.

An amplification of the CCNE1 gene and/or an expression level of CCNE1that is higher than a control expression level of CCNE1 isindicative/predictive that a human subject having or at risk ofdeveloping a disease or disorder associated with CDK2 will respond to aCDK2 inhibitor. In some embodiments, the expression level of CCNE1 maybe the level of CCNE1 mRNA. In other embodiments, the expression levelof CCNE1 may be the level of CCNE1 protein.

Other Biomarkers

In some embodiments, the contemplated biomarker may be p16 (also knownas cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4inhibitor A, multiple tumor suppressor 1, and p16-INK₄a), which acts asa negative regulator of the proliferation of normal cells by interactingwith CDK4 and CDK6. In other embodiments, the contemplated biomarker maybe phosphorylation of Rb at the serine corresponding to amino acidposition 780. Rb is a regulator of the cell cycle and acts as a tumorsuppressor. Rb is activated upon phosphorylation by cyclin D-CDK4/6 atSer780 and Ser795 and by cyclin E/CDK2 at Ser807 and Ser811.

The contemplated biomarker may also be selected from the groupconsisting of RB1, RBL1, RBL2, CDKN2A, CDKN1A, CDKN1B, FBXW7, CCNE1,CCNE2, CCNA1, CCNA2, CCND1, CCND2, CCND3, CDK2, CDK3, CDK4, CDK6,CDKN2A, CDNK1A, CDKN1B E2F1, E2F2, E2F3, MYC, MYCL, MYCN, EZH2, ER,HER2, HER3, HPV+, and EGFR.

Biological Samples

Suitable biological samples for the methods described herein include anysample that contains blood or tumor cells obtained or derived from thehuman subject in need of treatment. For example, a biological sample cancontain tumor cells from biopsy from a patient suffering from a solidtumor. A tumor biopsy can be obtained by a variety of means known in theart. Alternatively, a blood sample can be obtained from a patientsuffering from a hematological cancer.

A biological sample can be obtained from a human subject having,suspected of having, or at risk of developing, a disease or disorderassociated with CDK2. In some embodiments, the disease or disorderassociated with CDK2 is a cancer (such as those described supra).

Methods for obtaining and/or storing samples that preserve the activityor integrity of molecules (e.g., nucleic acids or proteins) in thesample are well known to those skilled in the art. For example, abiological sample can be further contacted with one or more additionalagents such as buffers and/or inhibitors, including one or more ofnuclease, protease, and phosphatase inhibitors, which preserve orminimize changes in the molecules in the sample.

Methods of Administration and Dosage Forms

The precise amount of compound administered to provide an “effectiveamount” to the subject will depend on the mode of administration, thetype, and severity of the cancer, and on the characteristics of thesubject, such as general health, age, sex, body weight, and tolerance todrugs. The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors. When administered in combinationwith other therapeutic agents, e.g., when administered in combinationwith an anti-cancer agent, an “effective amount” of any additionaltherapeutic agent(s) will depend on the type of drug used. Suitabledosages are known for approved therapeutic agents and can be adjusted bythe skilled artisan according to the condition of the subject, the typeof condition(s) being treated and the amount of a compound of Formula(I) or Formula (Ia) being used by following, for example, dosagesreported in the literature and recommended in the Physician’s DeskReference (57th Ed., 2003).

“Treating” or “treatment” refers to obtaining a desired pharmacologicaland/or physiological effect. The effect can be therapeutic, whichincludes achieving, partially or substantially, one or more of thefollowing results: partially or substantially reducing the extent of thedisease, condition or cancer; ameliorating or improving a clinicalsymptom or indicator associated with the disease, condition or cancer;delaying, inhibiting or decreasing the likelihood of the progression ofthe disease, condition or cancer; or decreasing the likelihood ofrecurrence of the disease, condition or cancer.

The term “effective amount” means an amount when administered to thesubject which results in beneficial or desired results, includingclinical results, e.g., inhibits, suppresses or reduces the symptoms ofthe condition being treated in the subject as compared to a control. Forexample, a therapeutically effective amount can be given in unit dosageform (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg toabout 5 grams per day; and in another alternatively from 10 mg to 1 gramper day).

The terms “administer”, “administering”, “administration”, and the like,as used herein, refer to methods that may be used to enable delivery ofcompositions to the desired site of biological action. These methodsinclude, but are not limited to, intraarticular (in the joints),intravenous, intramuscular, intratumoral, intradermal, intraperitoneal,subcutaneous, orally, topically, intrathecally, inhalationally,transdermally, rectally, and the like. Administration techniques thatcan be employed with the agents and methods described herein are foundin e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.; Pergamon; and Remington’s, Pharmaceutical Sciences (currentedition), Mack Publishing Co., Easton, Pa.

In addition, a compound of the disclosure, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition of the disclosure can beco-administered with other therapeutic agents. As used herein, the terms“co-administration”, “administered in combination with”, and theirgrammatical equivalents, are meant to encompass administration of two ormore therapeutic agents to a single subject, and are intended to includetreatment regimens in which the agents are administered by the same ordifferent route of administration or at the same or different times. Insome embodiments the one or more compounds of the disclosure, apharmaceutically acceptable salt thereof or a pharmaceutical compositionof the disclosure will be co-administered with other agents. These termsencompass administration of two or more agents to the subject so thatboth agents and/or their metabolites are present in the subject at thesame time. They include simultaneous administration in separatecompositions, administration at different times in separatecompositions, and/or administration in a composition in which bothagents are present. Thus, in some embodiments, the compounds describedherein and the other agent(s) are administered in a single composition.In some embodiments, the compounds described herein and the otheragent(s) are admixed in the composition.

The particular mode of administration and the dosage regimen will beselected by the attending clinician, taking into account the particularsof the case (e.g. the subject, the disease, the disease state involved,the particular treatment). Treatment can involve daily or multi-daily orless than daily (such as weekly or monthly etc.) doses over a period ofa few days to months, or even years. However, a person of ordinary skillin the art would immediately recognize appropriate and/or equivalentdoses looking at dosages of approved compositions for treating a diseaseusing the disclosed CDK2 inhibitors for guidance.

The compounds of the disclosure or a pharmaceutically acceptable saltthereof can be administered to a patient in a variety of forms dependingon the selected route of administration, as will be understood by thoseskilled in the art. The compounds of the present teachings may beadministered, for example, by oral, parenteral, buccal, sublingual,nasal, rectal, patch, pump or transdermal administration and thepharmaceutical compositions formulated accordingly. Parenteraladministration includes intravenous, intraperitoneal, subcutaneous,intramuscular, transepithelial, nasal, intrapulmonary, intrathecal,rectal and topical modes of administration. Parenteral administrationcan be by continuous infusion over a selected period of time.

The pharmaceutical composition of the disclosure is formulated to becompatible with its intended route of administration. In an embodiment,the composition is formulated in accordance with routine procedures as apharmaceutical composition adapted for intravenous, subcutaneous,intramuscular, oral, intranasal, or topical administration to humanbeings. In preferred embodiments, the pharmaceutical composition isformulated for intravenous administration.

Typically, for oral therapeutic administration, a compound of thedisclosure or a pharmaceutically acceptable salt thereof may beincorporated with excipient and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like.

Typically for parenteral administration, solutions of a compound of thedisclosure can generally or a pharmaceutically acceptable salt thereofbe prepared in water suitably mixed with a surfactant such ashydroxypropylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, DMSO and mixtures thereof with or withoutalcohol, and in oils. Under ordinary conditions of storage and use,these preparations contain a preservative to prevent the growth ofmicroorganisms.

Typically, for injectable use, sterile aqueous solutions or dispersionof, and sterile powders of, a compound of the disclosure for theextemporaneous preparation of sterile injectable solutions ordispersions are appropriate.

The following examples are intended to be illustrative and are notintended to be limiting in any way to the scope of the disclosure.

EXEMPLIFICATION Preparation of Exemplary Compounds Definitions

-   AcOH means acetic acid;-   t-AmOH means tert-amyl alcohol;-   Aq. means aqueous;-   Bn means benzyl;-   Boc means tert-butoxy carbonyl;-   Boc₂O means di-tert-butyl dicarbonate;-   (BPin)₂ means 4,4,4′,4′,5,5,5′,5′ -Octamethyl-2,2′    -bi-1,3,2-dioxaborolane;-   br means broad;-   Brettphos means 2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′    -triisopropyl-1,1′ -biphenyl;-   BrettPhos Pd G3 means    [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′ -triisopropyl-1,1′    -biphenyl)-2-(2′ -amino-1,1′ -biphenyl)]palladium(II)    methanesulfonate;-   n-BuOH means butan-1-ol;-   t-BuOH means tertiary butanol;-   t-BuOK means potassium tert-butoxide;-   t-BuXPhos Pd G3 means (2-Di-tert-butylphosphino-2′,4′,6′    -triisopropyl-1,1′ -biphenyl)-2-(2′ -amino-1,1′ -biphenyl)    palladium(II) methanesulfonate;-   °C means degrees Celsius;-   CDCl₃ means deutero-chloroform;-   Cs₂CO₃ means cesium carbonate;-   CuCN means copper cyanide;-   δ means chemical shift;-   d means doublet;-   dd means doublet of doublets;-   dq means doublet of quartets;-   dt means doublet of triplets;-   DAST means Diethylaminosulfur trifluoride;-   DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene;-   DCM means dichloromethane;-   DEA means diethylamine;-   DEAD means diethyl azodicarboxylate;-   DIAD means diisopropyl azodicarboxylate;-   DIBAL-H means diisobutylaluminium hydride;-   DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine;-   DMA means N,N-Dimethylacetamide;-   DMF means N,N-dimethylformamide;-   DMSO means Dimethylsulfoxide;-   DMSO-d₆ means hexadeuterodimethyl sulfoxide;-   EA means ethyl acetate;-   Et means ethyl;-   Et₂O means diethyl ether;-   EtOAc means ethyl acetate;-   EtOH means ethanol;-   Eq. means equivalent;-   g means gram;-   HATU means    1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate;-   HBF₄ means tetrafluoroboric acid;-   HCl means hydrochloric acid;-   HCOH means formaldehyde;-   HCO₂H means formic acid;-   Hept means heptet;-   ¹H NMR means proton nuclear magnetic resonance;-   H₂O means water;-   H₂O₂ means hydrogen peroxide;-   HPLC means high pressure liquid chromatography;-   h means hour;-   IPA means 2-propanol;-   K₂CO₃ means potassium carbonate;-   KI means potassium iodide;-   KOH means potassium hydroxide;-   K₃PO₄ means potassium phosphate tribasic;-   L means litre;-   LCMS means liquid chromatography mass spectrometry;-   LDA means lithium diisopropylamide;-   LiAlH₄ means lithium aluminium hydride;-   LiOH means lithium hydroxide;-   m means multiplet;-   M means molar;-   Me means methyl;-   MeCN means acetonitrile;-   MeI means iodomethane;-   MeLi means methyl lithium;-   MeMgBr means methyl magnesium bromide;-   MeNH₂ means methylamine;-   MeOH means methanol;-   MeOH-d₄ means deutero-methanol;-   mg means milligram;-   MgSO₄ means magnesium sulfate;-   MHz means mega Hertz;-   mins means minutes;-   mL means millilitres;-   mmol means millimole;-   MPLC means medium pressure liquid chromatography;-   MS m/z means mass spectrum peak;-   MTBE means methyl tert-butyl ether;-   N₂ means nitrogen;-   NaBH₄ means sodium borohydride;-   Na₂CO₃ means sodium carbonate;-   NaH means sodium hydride;-   NaHCO₃ means sodium bicarbonate;-   NaOH means sodium hydroxide;-   Na₂SO₄ means sodium sulfate;-   NCS means N-chlorosuccinimide;-   NH₃ means ammonia;-   NH₄Cl means ammonium chloride;-   NH₄HCO₃ means ammonium carbonate;-   NH₂OH means hydroxylamine;-   NH₄OH is ammonium hydroxide;-   NMP means N-methyl pyrrolidine;-   PE means petroleum ether;-   Pd(amphos)Cl₂ means    Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II);-   Pd(t-Bu₃P)₂ means Bis(tri-tert-butylphosphine)palladium(0);-   Pd(OAc) means palladium acetate;-   Pd₂(dba)₃ means tris(dibenzylideneacetone)dipalladium (0);-   Pd(dppf)Cl₂ means    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II);-   Pd(PPh₃)₄ means tetrakis(triphenylphosphine)palladium(0);-   Pd(PPh₃)Cl₂ means Palladium(II)bis(triphenylphosphine) dichloride;-   Pd/C means palladium on charcoal;-   Pd(OH)₂ means palladium hydroxide;-   PPh₃ means triphenylphosphine;-   q means quartet;-   rt means room temperature;-   RT means retention time;-   RuPhos Pd G3 means (2-dicyclohexylphosphino-2′,6′ -diisopropoxy-1,1′    -biphenyl)[2-(2’ -amino-1,1′ -biphenyl)]palladium(II)    methanesulfonate;-   s means singlet;-   sat. means saturated;-   SFC means supercritical fluid chromatography;-   soln. means solution;-   t means triplet;-   TBAF means Tetrabutylammonium fluoride;-   TBDMSCl means tert-Butyl(chloro)dimethylsilane;-   TEA means triethylamine;-   TFA means trifluoroacetic acid;-   TfOH means trifluoroethanesulfonic acid;-   THF means tetrahydrofuran;-   TLC means thin layer chromatography;-   TsOH means p-toluenesulfonic acid;-   µL means micro litres;-   µmol means micromole;-   Xantphos means 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene;-   Xantphos Pd G2 means    Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′    -amino-1,1′ -biphenyl)]palladium(II);-   Xantphos Pd G3 means    [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′ -amino-1,1′    -biphenyl)]palladium(II) methanesulfonate;-   XPhos Pd G2 means Chloro(2-dicyclohexylphosphino-2′,4′,6′    -triisopropyl-1,1′ -biphenyl)[2-(2′ -amino-1,1′    -biphenyl)]palladium(II).

Methods for preparing compounds of the invention can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), intermediates, orproducts at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent’s freezingtemperature to the solvent’s boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Wuts and Greene,Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons: NewJersey, (2014), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., ¹Hor 13C), infrared (IR) spectroscopy, spectrophotometry (e.g.,UV-visible), mass spectrometry (MS), or by chromatographic methods suchas high performance liquid chromatography (HPLC) or thin layerchromatography (TLC). Analytical instruments and methods for compoundcharacterization:

LC-MS: The liquid chromatography-mass spectrometry (LC-MS) data wereobtained with an Agilent Technologies 1200 Series LCMSD utilizingAPI-ESI ionization fitted with a reverse-phase column (Sunfire C18, 3.5um particle size, 4.6 x 50 mm dimensions) at 50° C. The mobile phaseconsisted of a mixture of solvent 0.01% TFA in water and 0.01% TFA inacetonitrile. A constant gradient from 5% increase to 95% organic within1.3 min, 95% organic for 1.7 min was utilized. The flow rate wasconstant at 2 mL/min. Alternatively, the liquid chromatography-massspectrometry (LC-MS) data were obtained with a Agilent Technologies 1200Series LCMSD utilizing API-ESI ionization utilizing ESI ionizationfitted with a reverse-phase column (XBridge C18, 3.5 um particle size,4.6 x 50 mm dimensions) at 45° C. The mobile phase consisted of amixture of solvent 10 mM NH4HCO3 in water and acetonitrile. A constantgradient from 5% increase to 95% organic within 1.4 min, 95% organic for1.6 min was utilized. The flow rate was constant at 1.8 mL/min.

Prep LC-MS: Preparative HPLC was performed on a Gilson 281 Preparativesystem fitted with a Welch Xtimate 10u C18 100A, AXIA packed, 250 x 21.2mm reverse-phase column at 20° C. The mobile phase consisted of amixture of solvent 0.1% formic acid in water and 0.1% formic acid inacetonitrile. A constant gradient from 70% aqueous/30% organic to 30%aqueous/70% organic mobile phase over the course of 15 minutes wasutilized. The flow rate was constant at 30 mL/min. Alternatively, fittedwith Column: Welch Xtimate 10u C18 21.2*250 mm, 10 um; The mobile phaseconsisted of a mixture of solvent Water (10 mmol/L NH4HCO3+0.05%NH3.H2O)and acetonitrile. A constant gradient from 70% aqueous/30% organic to30% aqueous/70% organic mobile phase over the course of 15 minutes wasutilized. The flow rate was constant at 30 mL/min.

Silica gel chromatography: Silica gel chromatography was performed on aBiotage® Isolera One unit, or a Biotage® Isolera Prime unit.

Proton NMR: ¹H NMR spectra were obtained with a Bruker AVANCE III 400MHz, 400 MHz NMR instrument (acquisition time = 3.16 seconds with a 1second delay; 8 to 32 scans) or a Bruker AVANCE III 400 MHz, 400 MHz NMRinstrument (acquisition time = 3.98 seconds with a 1 second delay; 8 to32 scans) or a Bruker AVANCE III 500 MHz, 500 MHz NMR instrument(acquisition time = 3.17 seconds with a 1 second delay; 8 to 32 scans).Unless otherwise indicated, all protons were reported in DMSO-d6 solventas parts-per million (ppm) with respect to residual DMSO (2.50 ppm).

SFC: Waters Preparative system(SFC80, SFC150, SFC200, SFC350 ).

Chiral-HPLC: Gilson 281(vendor: GILSON)

One of ordinary skill in the art will recognize that modifications ofthe gradient, column length, and flow rate are possible and that someconditions may be more suitable for compound characterization thanothers, depending on the chemical species being analyzed.

The following codes refer to the preparative HPLC conditions used asindicated in the Preferred Examples and Preparation sections. Individualgradients were optimized for each compound as appropriate.

Prep-HPLC Code Conditions HPLC-1 Xtimate 150A, 21.2 x 250 mm, 10 mm;15-95% MeCN/H₂O (0.1% NH₄HCO₃) HPLC-2 Xtimate 150A, 21.2 x 250 mm, 10mm; 15-95% MeCN/H₂O (0.1% NH₄HCO₃ + NH₄OH) HPLC-3 Xtimate 150A, 21.2 x250 mm, 10 mm; 15-95% MeCN/H₂O (10 mM NH₄HCO₃) HPLC-4 Xtimate 150A, 21.2x 250 mm, 10 mm; 15-95% MeCN/H2O (10 mM NH₄HCO₃ + NH₄OH) HPLC-5 Xtimate150A, 21.2 x 250 mm, 10 mm; 15-95% MeCN/H₂O (0.1% HCO₂H)

General Schemes

According to a first process, compounds of Formula (1′) may be preparedfrom the compounds of Formulae (II′) and (III′), as illustrated byScheme 1.

The compound of Formula (I′) may be prepared from the compounds ofFormulae (II′) and (III′) according to process step (a) aBuchwald-Hartwig cross-coupling. Typical conditions comprise, reactionof the amine of Formula (III′) with the chloride of Formula (II′) in thepresence of a suitable inorganic base, a suitable catalyst in a suitablesolvent at elevated temperature. Preferred conditions comprise, reactionof the compounds of Formulae (II′) and (III′) in the presence of,BrettPhos Pd G3, tBuBrettPhos Pd G3, BrettPhos Pd G4, tBuBrettPhos PdG4, t-BuXphos Pd G3, tBuXPhos Pd G4, or Xantphos Pd G3 orPd₂(dba)₃/tBuXPhos in the presence of a suitable base such as Cs₂CO₃K₂CO₃, K₃PO₄ or KOAc in a suitable solvent such as dioxane, toluene,t-AmOH, NMP or DMF, at between 90° C. and 130° C.

According to a second process, the compound of Formula (II′) may beprepared from the compounds of Formulae (IV′) and (V′), as illustratedin Scheme 2.

The compound of Formula (II′), wherein at least one of R³ or R⁴ is H,may be prepared from the compounds of Formulae (IV′) and (V′) accordingto process step (b) a Mitsunobu reaction. Typical conditions comprisereaction of the compound of Formula (IV′) with the alcohol of Formula(V′) in the presence of a suitable azodicarboxylate, such as DIAD orDEAD, in the presence of PPh₃, in a suitable solvent such as THF ortoluene at between 0° C. and 80° C.

Alternatively, wherein, both R³ and R⁴ are not H, the compound ofFormula (II′) may be prepared from the compounds of Formulae (IV′) and(V′) according to process step (c), an alkylation reaction. Typicalconditions comprise reaction of the compounds of Formulae (IV′) and (V′)in the presence of an acid catalyst, such as TfOH, in a suitable polaraprotic solvent, such as DCM at between 0° C. and rt.

According to a third process, the compound of Formula (II′) may beprepared from the compounds of Formulae (IV′) and (VI′), as illustratedin Scheme 3.

The compound of Formula (II′) may be prepared from the compounds ofFormulae (IV′) and (VI′) by process step (d), an epoxide openingreaction. Typical conditions comprise reaction of the compounds ofFormulae (IV′) and (VI′′) in the presence of a suitable inorganic base,such as K₂CO₃, in a suitable polar aprotic solvent, such as MeCN atbetween rt and elevated temperature, such as 90° C.

The compounds of Formulae (II′), (IV′), (V′) and (VI′) are eithercommercially available or may be prepared by analogy to methods known inthe literature, or the methods described in the Experimental sectionbelow.

Compounds of Formulae (I′), (II′) and (IV′) may be converted toalternative compounds of Formulae (I′), (II′) and (IV′) by standardchemical transformations, known to those skilled in the art. Examples ofthese transformations include, but are not limited to:

Reduction of a ketone to a secondary alcohol using NaBH₄, fluorination,using selectflor or DAST, chlorination using NCS in conjunction withHBF₄, transformation of aryl iodides to ketones using Stille methodologyor transformation of an iodo group to a nitrile, using CuCN.

It will be appreciated by those skilled in the art, that it may benecessary to utilise a suitable protecting group strategy for thepreparation of compounds of Formula (1′). Typical protecting groups maycomprise, carbamate and preferably Boc for the protection of amines,including pyrazoles, or a TIPS or benzyl group for the protection of aprimary or secondary alcohol,

It will be further appreciated that it may be necessary or desirable tocarry out the transformations in a different order from that describedin the schemes, or to modify one or more of the transformations, toprovide the desired compound of the invention.

Preparations Preparation 1. 3,6-dichloro-1H-pyrazolo[3,4-blpyrazine

BF₄ (852 mg, 9.71 mmol) followed by NCS (864 mg, 6.47 mmol) were addedto a suspension of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (500 mg, 6.47mmol) in MeCN (12 mL) and the reaction heated at 90° C. overnight. Thecooled mixture was concentrated in vacuo and 1 M NaOH (9.5 mL) was addedto neutralize the solution. The resulting suspension was filtered off,washed with water, and dried to afford the title compound, 596 mg, as apale-yellow solid. LCMS m/z = 191 [M+H]⁺.

Preparation 2. 6-chloro-3-iodo-1H-pyrazolo[3,4-blpyrazine

HBF₄ (1.704 g, 194 mmol) and 1-iodopyrrolidine-2,5-dione (2.91 g, 12.9mmol) were added to a solution of 6-chloro-1H-pyrazol[3,4-b]pyrazine(1.0 g, 6.47 mmol) in MeCN and the reaction heated to 80° C. for 2 h.The cooled reaction was concentrated in vacuo, the residue diluted withwater, then NaOH (2.5 mL) and sodium thiosulfate added until the reddishcolor had turned to consistently pale yellow. The mixture was filtered,washed with water and dried to give the title compound, 1.71 g, 94%yield. LCMS m/z = 281 [M+H]⁺.

Preparation 3. 6-chloro-3-fluoro-1H-pyrazolo[3,4-blpyrazine

A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (500 mg, 3.23 mmol) andSelectfluor (2.28 g, 6.46 mmol) in MeCN (8 mL) and water (2 mL) wasstirred at 100° C. in a sealed tube for 15 h. The cooled reactionmixture was concentrated in vacuo and the residue was purified by flashchromatography on silica gel eluting with EtOAc/PE (1/1) to afford thetitle compound (120 mg, 22% yield) as a yellow solid. LCMS m/z = 173[M+H]⁺.

Preparation 4. Methyl (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate

A mixture of methyl (S)-2-hydroxypropanoate (10.0 g, 96.1 mmol),3,4-dihydro-2H-pyran (8.08 g, 96.1 mmol) and TsOH (1.65 g, 9.61 mmol) inDCM (100 mL) was stirred for 3 h. The reaction mixture was washed withwater and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by flash chromatography on silica gel elutingwith EtOAc/PE (1/30) to give the title compound (9.70 g, 53% yield) as ayellow oil.

Preparation 5. Methyl (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate

The title compound was obtained as a yellow oil, 97.7 g, 53% from methyl(R)-2-hydroxypropanoate, following the procedure described inPreparation 4.

Preparation 6. (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol

To a mixture of methyl (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate(Preparation 4, 700 mg, 3.72 mmol) in toluene (30 mL) was added dropwiseDIBAL-H (1.5 M/toluene, 2.8 mL, 4.2 mmol) at -78° C. under N₂ and themixture stirred at -70° C. for 30 min. Ethyl magnesium bromide (1.0 M inTHF, 6.0 mL, 6.0 mmol) was added, the reaction stirred at -70° C. for 20min and slowly warmed to rt. The reaction mixture was poured intoice-water and aqueous HCl (10%) added until all precipitate wasdissolved. The aqueous phase was extracted with THF/toluene, and thecombined organic layers were washed with water, aqueous NaOH (1 M) andbrine, dried over MgSO₄, filtered and the filtrate was concentrated invacuo. The residue was purified by flash chromatography on silica geleluting with EtOAc/PE (⅕) to give the title compound (600 mg, 85% yield)as a yellow oil.

Preparation 7. (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol

The title compound was obtained as a yellow oil, 600 mg, 85%, frommethyl (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (Preparation 5),following the procedure described in Preparation 7.

Preparation 8. 4-vinyltetrahydro-2H-pyran

To a mixture of sodium hydride (2.08 g, 52.5 mmol) in THF (25 mL) wasadded methyltriphenylphosphanium bromide (18.70 g, 52.5 mmol), and themixture heated at reflux for 2 h. After cooling to rt,oxane-4-carbaldehyde (5.00 g, 43.8 mmol) was added and the reactionstirred at rt for 15 h. The reaction was diluted with ether and washedwith aq. NaHCO₃ and brine. The organic layer was concentrated in vacuoand the residue purified by flash chromatography on silica gel elutingwith EtOAc/PE (⅕) to give the title compound (0.9 g, 18% yield) as acolorless oil. 1H-NMR (500 MHz, DMSO-d₆) δ ppm 5.83-5.75 (m, 1H),5.02-4.93 (m, 2H), 3.85-3.82 (m, 2H), 3.34-3.29 (m, 2H), 2.19-2.14 (m,1H), 1.32-1.24 (m, 4H).

Preparation 9. (S)-1-(tetrahydro-2H-pyran-4-yl)ethane-1,2-diol

To a mixture of AD-mix-alpha (12.7 g, 16 mmol) in t-BuOH:H₂O 1:1 (150mL) was added 4-vinyltetrahydro-2H-pyran (Preparation 8, 0.9 g, 8 mmol)at 0° C. and the solution was allowed to warm to rt. The reaction wascovered with aluminum foil to exclude light and then stirred at rt fortwo days. The mixture was cooled to 0° C., sodium sulfite (15 g) wasadded and the mixture stirred at rt for 1 h. EtOAc was added, the layerswere separated and the aqueous layer extracted with EtOAc (2x) andDCM:MeOH 10:1. The combined organic layers were dried, and evaporatedunder reduced pressure to give the title compound (0.6 g, 51% yield) asa yellow oil. LCMS m/z = 147 [M+H]⁺.

Preparation 10.(S)-1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethan-1-ol

To a mixture of (1S)-1-(tetrahydro-2H-pyran-4-yl)ethane-1,2-diol(Preparation 9, 600 mg, 4.10 mmol) and 1H-imidazole (830 mg, 12.2 mmol)in DCM (6 mL) was added chlorotris(propan-2-yl)silane (790 mg, 4.10mmol) at 0° C., and the reaction stirred at rt for 15 h. The reactionmixture was diluted with DCM and washed with water. The organic layerwas evaporated in vacuo and the residue was purified by flashchromatography on silica gel eluting with EtOAc/PE (⅕) to give the titlecompound (0.7 g, 56% yield) as a yellow oil. LCMS m/z = 303 [M+H]⁺.

Preparation 11. 2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol

A mixture of tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 4.38 mmol),(difluoromethyl)trimethylsilane (543 mg, 4.38 mmol) and CsF (1.99 g,13.14 mmol) in DMF (5 mL) was stirred overnight. TBAF (5 equiv.) wasadded and the reaction stirred at rt for 1 h. The reaction was quenchedwith water and extracted with EtOAc. The combined organic layer waswashed with water and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with EtOAc/PE (¼) to give the title compound (230mg, 31% yield). LCMS m/z =167 [M+H]⁺.

Preparation 12. 1-(tetrahydro-2H-pyran-3-yl)ethan-1-ol

To a solution of tetrahydro-2H-pyran-3-carbaldehyde (500 mg, 4.38 mmol)in THF (20 mL) was added MeMgBr (1 M in THF, 4.4 mL, 4.4 mmol) at 0° C.and the reaction stirred for 30 min at this temperature and then allowedto warm to rt and stirred for a further 2 h. The resulting mixture wasquenched with water and extracted with EtOAc. The organic layer wasevaporated under reduced pressure to give the crude title compound whichwas used in next step directly.

Preparation 13. 2-(oxiran-2-yl)pyridine

To a solution of H₂O (25 mL) and dioxane (90 mL) was added2-ethenylpyridine (14 g, 133 mmol) and AcOH (7.98 g, 133 mmol), then1-bromopyrrolidine-2,5-dione (25.9 g, 146 mmol) was slowly added and themixture stirred for 1 h. Na₂CO₃ (42.2 g, 399 mmol) was added and thereaction stirred for 1 h. The mixture was diluted with EtOAc and washedwith water. The organic layer was concentrated in vacuo to about 20 mL,and then purified by flash chromatography on silica gel eluting withEtOAc/PE (½) to give the title compound (14 g, 87%) as a yellow oil.LCMS m/z = 122 [M+H]⁺.

Preparation 14. 3-(oxiran-2-yl)pyridine

The title compound was obtained as a yellow oil, 4 g, 35% yield, from3-ethenylpyridine, following the procedure described in Preparation 13.LCMS m/z = 122 [M+H]⁺.

Preparation 15. 2-fluoro-1-(pyridin-2-yl)ethan-1-ol

A mixture of 2-(oxiran-2-yl)pyridine (Preparation 13, 8 g, 66.0 mmol)and 1 M TBAF/THF (120 mL) was heated under reflux for 1 day. The cooledreaction mixture was diluted with EtOAc and washed with water. Theorganic layer was concentrated in vacuo to about 20 mL, and thenpurified by flash chromatography on silica gel eluting with EtOAc/PE (⅓)to give the title compound (1 g, 11 % yield) as a yellow oil. LCMS m/z =142 [M+H]⁺.

Preparation 16. 2-fluoro-1-(pyridin-3-yl)ethan-1-ol

The title compound was obtained as a yellow oil, 120 mg, 3% yield from3-(oxiran-2-yl)pyridine (Preparation 14), following the proceduredescribed in Preparation 15. LCMS m/z = 142 [M+H]⁺.

Preparation 17. 1-(4-fluoropyridin-3-yl)ethan-1-one

Part 1. To a solution of 4-fluoropyridine-3-carboxylic acid (300 mg,2.12 mmol), methoxy(methyl)amine hydrochloride (310 mg, 3.18 mmol) andDIPEA (548 mg, 4.24 mmol) in DMF (5 mL) was added HATU (965 mg, 2.54mmol) and the reaction stirred at rt for 15 h. The reaction mixture wasconcentrated in vacuo, and the residue purified by flash chromatographyon silica gel eluting with EtOAc/PE (1/1) to give4-fluoro-N-methoxy-N-methylnicotinamide (250 mg, 64% yield) as a yellowsolid.

Part 2. To a mixture of4-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (Part 1, 200 mg, 1.08mmol) in THF (5 mL) was added MeMgBr (2M in THF, 2.2 mL, 4.4 mmol) at 0°C. and the reaction stirred at rt for 2 h. The reaction mixture wasquenched with saturated aqueous NH₄Cl and extracted with EtOAc. Theorganic layer was concentrated, and the residue was purified by flashchromatography on silica gel eluting with EtOAc/PE (1/1) to give thetitle compound (150 mg, 80% yield) as a yellow oil. LCMS m/z = 140[M+H]⁺.

Preparation 18. 1-(4-fluoropyridin-3-yl)ethan-1-ol

To a mixture of 1-(4-fluoropyridin-3-yl)ethan-1-one (Preparation 17, 150mg, 1.07 mmol) in MeOH (4 mL) was added NaBH₄ (162 mg, 4.28 mmol) andthe reaction stirred at rt for 10 min. The reaction mixture was dilutedwith EtOAc and washed with water. The organic layer was concentrated invacuo, and the residue was purified by flash chromatography on silicagel eluting with EtOAc/PE (2/1) to give the title compound (100 mg, 66%yield) as a yellow oil. LCMS m/z = 142 [M+H]⁺.

Preparation 19. 1-(4-fluoropyridin-2-yl)ethan-1-ol

To a solution of 4-fluoropyridine-2-carbaldehyde (2.5 g, 19.9 mmol) inTHF (50 mL) at 0° C., was added MeMgBr (2M in THF, 15 mL, 30 mmol) andthe reaction stirred for 2 h. The reaction mixture was quenched withsaturated aqueous NH₄Cl and extracted with EtOAc. The organic layer wasconcentrated in vacuo and the residue was purified by flashchromatography on silica gel eluting with EtOAc/PE (2/1) to afford thetitle compound (1.7 g, 64%) as a yellow oil. LCMS m/z = 142 [M+H]⁺.

Preparation 20 and 21. (S)-2-fluoro-1-phenylethan-1-ol and(R)-2-fluoro-1-phenylethan-1-ol

A mixture of styrene (10.0 g, 96.01 mmol) and selectfluor reagent (51.0g, 144.02 mmol) in MeCN/H₂O (100 mL/50 mL) was heated at 90° C.overnight under N₂. The reaction mixture was concentrated in vacuo andthe residue was extracted with EtOAc. The combined organic layers werewashed with water and brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel eluting with EtOAc/PE (1/20-⅕) to give 2-fluoro-1-phenylethan-1-ol(2.50 g, 73% yield) as a yellow oil. 1H-NMR (400 MHz, DMSO-d₆) δ ppm:7.40-7.25 (m, 5H), 5.72 (d, 1H), 4.86-4.80 (m, 1H), 4.50-4.01 (m, 2H).

This was further purified by SFC using an OD-H 20 x 250 mm, 10 µm(Daicel) column, mobile phase: CO₂/ MeOH (0.2% MeOH/NH₃) = 85/15 at 70g/min to provide:

Enantiomer 1: (S)-2-fluoro-1-phenylethan-1-ol or(R)-2-fluoro-1-phenylethan-1-ol, 300 mg.

Enantiomer 2: (R)-2-fluoro-1-phenylethan-1-ol or(S)-2-fluoro-1-phenylethan-1-ol (300 mg).

Preparation 22. Oxetan-3-yl(phenyl)methanol

To a solution of oxetane-3-carbaldehyde (500 mg, 5.80 mmol) in THF (10mL) was added phenyl lithium (13 mL, 17.4 mmol) slowly at -78° C. underN₂ and the reaction stirred at -78° C. for 30 min and a further 2 h atrt. The reaction mixture was quenched with sat. aq. NH₄Cl solution andextracted with EtOAc. The organic layer was evaporated under reducedpressure to give the title compound (1.2 g, crude).

Preparation 23. (S)-1-phenyl-2-((triisopropylsilyl)oxy)ethan-1-ol

To a mixture of (S)-1-phenylethane-1,2-diol (1.50 g, 10.8 mmol) and1H-imidazole (2.20 g, 32.5 mmol) in DMF (10 mL) was added dropwisechlorotriisopropylsilane (2.09 g, 10.8 mmol) at 25° C., and the reactionstirred overnight. The reaction was diluted with DCM, washed with waterand brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withEtOAc/PE (1/30) to give the title compound (900 mg, 28% yield) as ayellow oil.

Preparation 24. 4-((triisopropylsilyl)oxy)butan-2-ol

To a mixture of butane-1,3-diol (2 g, 22.1 mmol) and 1H-imidazole (4.51g, 66.3 mmol) in DCM (30 mL) was added chlorotris(propan-2-yl)silane(4.26 g, 22.1 mmol) at 0° C., and the reaction stirred at rt for 15 h.The reaction mixture was diluted with DCM, washedwith water and theorganic layer was concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with EtOAc/PE (⅕) to give thetitle compound (2 g, 37% yield) as a colorless oil. LCMS m/z = 247[M+H]⁺.

Preparation 25. (S)-1-(pyridin-3-yl)ethane-1,2-diol

The title compound was obtained as a yellow oil, 700 mg, 38% yield, from3-vinylpyridine following a similar procedure to that described inPreparation 9. LCMS m/z = 140 [M+H]⁺.

Preparation 26.(S)-1-(pyridin-3-yl)-2-((triisopropylsilyl)oxy)ethan-1-ol

The title compound was obtained as a yellow oil, 700 mg, 47% yield, from(1S)-1-(pyridin-3-yl)ethane-1,2-diol (Preparation 25), following themethod described in Preparation 23. LCMS m/z = 296 [M+H]⁺.

Preparation 27.(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methanol

To a solution of ethyl2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate(300 mg, 1.24 mmol) in THF (20 mL) was added LiAlH₄ (150 mg, 3.72 mmol)at 0° C. and the reaction stirred for 18 h. The reaction mixture wasquenched with Na₂SO₄· 10H₂O, the mixture filtered and the filtrate wasevaporated under reduced pressure to give the title compound (206 mg,crude) as a yellow oil which was used in the next step directly.

Preparation 28. Methyl 2-(hydroxymethyl)-4-methyl-4-nitropentanoate

To a solution of 2-nitropropane (917 mg, 10.3 mmol) in THF (8 mL) wasadded DBU (131 mg, 0.861 mmol). After stirring at 65° C. for 10 mins,methyl 2-(hydroxymethyl)prop-2-enoate (1 g, 8.61 mmol) was addeddropwise. The reaction mixture was stirred at 80° C. for 2 h, then at25° C. for 16 h. The reaction was diluted with EtOAc, washed with waterand brine and the organic layer was concentrated in vacuo. The residuewas purified by flash chromatography on silica gel eluting with EtOAc/PE(¼) to afford the title compound (900 mg, 51% yield) as a yellow oil.

Preparation 29. 3-(hydroxymethyl)-5,5-dimethylpyrrolidin-2-one

To a solution of methyl 2-(hydroxymethyl)-4-methyl-4-nitropentanoate(Preparation 28, 350 mg, 1.70 mmol) in EtOH (5 mL) was added Raney Ni(100 mg) and the reaction was stirred at 25° C. under 2 bar of H₂ for 16h. The reaction was filtered and the filtrate was evaporated underreduced pressure to afford the title compound (200 mg, 82% yield) as awhite solid. LCMS m/z =144 [M+H]⁺.

Preparation 30. Tert-butyl3-amino-5-(difluoromethoxy)-1H-pyrazole-1-carboxylate

To a solution of 5-(difluoromethoxy)-1H-pyrazol-3-amine (24 g, 64.39mmol, 40% purity) in DCM (200 mL), was added KOH (4.5 M, 114.47 mL) andBoc₂O (28.10 g, 128.77 mmol) and the reaction was heated at 50° C. for16 h. The reaction mixture was extracted with DCM (40 mL x 3), thecombined organic layers were washed with brine (40 mL x 3), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash silica gel chromatography (ISCO 0-13% EtOAc/PE) togive the title compound (5 g, 31.16% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.52 -7.11 (m, 1H), 6.66 (br s, 2H), 5.12 (s,1H), 1.52 - 1.61 (m, 9H).

Preparation 31.(S)-6-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (400 mg, 2.59 mmol),(R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (438 mg, 3.11 mmol) and PPh₃ (815mg, 2.59 mmol) in THF (8 mL) was cooled in an ice bath. DIAD (628 mg,3.11 mmol) was added dropwise and the reaction allowed to warm slowly tort and stirred overnight. The mixture was concentrated in vacuo and theresidue pre-loaded onto silica gel and purified by Isco chromatography(0 to 60% EtOAc/Hex) to give a colorless oil. This was further purifiedby reverse phase Isco (0 to 100% MeCN/0.1% aq. TFA). The product wasneutralized using NaHCO₃ and extracted with DCM (3x). The combinedorganic extracts were evaporated under reduced pressure to afford thetitle compound as a colorless oil, 320 mg, 44.6% yield. LCMS m/z = 278[M+H]⁺.

Preparation 32.(R)-6-chloro-1-(1-cyclopropylethyl)-1H-pyrazolo[3,4-bipyrazine

A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol),(S)-1-cyclopropylethan-1-ol (167 mg, 1.94 mmol) and PPh₃ (611 mg, 2.329mmol) in THF was cooled in an ice bath. DIAD (471 mg, 2.329 mmol) wasadded dropwise and the reaction allowed to warm slowly to rt. Themixture was concentrated in vacuo and the residue pre-loaded onto silicagel and purified by Isco chromatography (0 to 60% EtOAc/Hex) to give acolorless oil. This was further purified by reverse phase Isco (0 to100% MeCN/0.1% aq. TFA) to afford the title compound as a colorless oil,70 mg.

Preparation 33.(S)-6-chloro-1-(1-cyclopropylethyl)-1H-pyrazolo[3,4-bipyrazine

The title compound was obtained as a colorless oil, 152 mg, 35.2% yield,from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and(R)-1-cyclopropylethan-1-ol, following a simialr procedure to thatdescribed in Preparation 32. ¹H NMR (500 MHz, CDCl₃) δ: 8.51 (d, 1H),8.28 (s, 1H), 4.22 (p, 1H), 1.71 (dd, 3H), 0.70 (p, 1H), 0.41 (t, 2H),0.35 (t, 2H).

Preparation 34.4-((6-chloro-1H-pyrazolo[3,4-blpyrazin-1-yl)methyl)thiazole

The title compound was obtained, 242 mg, 49.5% yield, as a colorless oilthat solidifed on standing, from 6-chloro-1H-pyrazolo[3,4-b]pyrazine andthiazol-4-ylmethanol, following a similar procedure to that described inPreparation 32. LCMS m/z = 252, 253 [M+H]⁺.

Preparation 35.5-((6-chloro-1H-pyrazolo[3,4-blpyrazin-1-yl)methyl)thiazole

The title compound was obtained, 243 mg, 49.5% yield, as a white solid,from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and thiazol-5-ylmethanol,following a similar procedure to that described in Preparation 32. LCMSm/z = 252, 253 [M+H]⁺.

Preparation 36.6-chloro-1-((2-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (200 mg, 1.294 mmol),(2-fluoropyridin-3-yl)methanol (197 mg, 1.553 mmol) and PPh₃ (407 mg,1.553 mmol) in THF (5 mL) was cooled in an ice bath. DIAD (314 mg, 1.553mmol) was added dropwise and the reaction allowed to warm slowly to rt.The mixture was concentrated in vacuo, the residue pre-loaded ontosilica gel and purified by Isco chromatography (0 to 100% EtOAc/Hex) togive the title compound, as a colorless oil, 216 mg, 63.5% yield, thatsolidified on standing. LCMS m/z = 264 [M+H]⁺.

Preparations 37-57

The compounds in the following table were prepared from6-chloro-1H-pyrazolo[3,4-b]pyrazine and the appropriate alcohol,following a similar procedure to that described in Preparation 36.

Preparation No. Name/Structure/Alcohol/Data 37(R)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (S)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol 250 mg, 83% yield,as a white solid. LCMS m/z = 267 [M+H]⁺ 386-chloro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: pyridin-3-methanol 153 mg, 38.5% yield, colorless oil thatsolidified on standing. LCMS m/z = 247 [M+H]⁺ 391-benzyl-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: benzyl alcohol 201 mg, 50.8% yield, as a colorless oil thatsolidified on standing. LCMS m/z = 245 [M+H]⁺ 406-chloro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (2-fluorophenyl)methanol 243 mg, 71.5% yield, as a colorlessoil that solidifed on standing. 1H NMR (500 MHz, DMSO-d₆) δ: 12.24 (s,1H), 10.85 (s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 7.37 —- 7.32 (m, 1H),7.24 — 7.10 (m, 3H), 5.80 (s, 2H). 416-chloro-1-(3-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (3-fluorophenyl)methanol 193 mg, 56.8% yield, as a colorlessoil. LCMS m/z = 263, 264 [M+H]⁺ 426-chloro-1-(4-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (4-fluorophenyl)methanol 243 mg, 71.5% yield, as a colorlessoil. LCMS m/z = 263, 264 [M+H]⁺ 436-chloro-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (6-fluoropyridin-3-yl)methanol 170 mg, 49.8% yield, colorlessoil that solidified on standing. LCMS m/z = 264 [M+H]⁺ 446-chloro-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (5-fluoropyridin-3-yl)methanol 179 mg, 52.5% yield, as a whitesolid. LCMS m/z = 265 [M+H]⁺ 45(S)-6-chloro-1-(1-(3-fluorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(3-fluorophenyl)ethan-1-ol 216 mg, 60.3% yield aspale-yellow oil. LCMS m/z = 277, 278 [M+H]⁺ 46(S)-6-chloro-1-(1-(2-fluorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(2-fluorophenyl)ethan-1-ol 188 mg, 35% yield, pale yellowoil. LCMS m/z = 277 [M+H]⁺ 47(S)-6-chloro-1-(1-(4-fluorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(4-fluorophenyl)ethan-1-ol 276 mg, 51.4% yield, paleyellow oil. 1H NMR (500 Hz, CDCl₃) δ: 8.52 (s, 1H), 8.29 (s, 1H), 7.44(dd, 2H), 7.00 (dd, 2H), 6.16 (q, 1H), 2.00 (d, 3H). 48(S)-6-chloro-1-(1-(5-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(5-fluoropyridin-2-yl)ethan-1-ol 481 mg, 66.9% yield as acolorless viscous oil. LCMS m/z = 278, 279 [M+H]⁺ 49(S)-6-chloro-1-(1-(3-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(3-fluoropyridin-2-yl)ethan-1-ol 481 mg, 66.9% yield as acolorless viscous oil. LCMS m/z = 278, 279 [M+H]⁺ 506-chloro-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 4,4-difluorocyclohexan-1-ol 232 mg, 65.7% yield as a whitesolid. LCMS m/z = 273, 274 [M+H]⁺ 51(1s,4s)-4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol

Alcohol: (1r,4r)-cyclohexane-1,4-diol. 95 mg, 19.4% yield, as a whitesolid. LCMS m/z = 253 [M+H]⁺ 522-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)thiazole

Alcohol: thiazol-2-ylmethanol 243 mg, 49.7% yield as a viscous oil. LCMSm/z = 252, 253 [M+H]⁺ 53(S)-5-(1-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)ethyl)thiazole

Alcohol: (R)-1-(thiazol-5-yl)ethan-1-ol 379 mg, 55.1% yield as apale-yellow oil. LCMS m/z = 266 [M+H]⁺ 54(S)-6-chloro-1-(1-(2-methoxypyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(2-methoxypyridin-3-yl)ethan-1-ol 437 mg, 58.3% yield asa white solid. LCMS m/z = 290 [M+H]⁺ 55(S)-6-chloro-1-(1-(2-chloropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(2 chloropyridin-3-yl)ethan-1-ol 473 mg, 62.1% yield as awhite solid. LCMS m/z = 296 [M+H]⁺ 566-chloro-1-(2,2-difluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 2,2-difluoro-1-(pyridin-2-yl)ethan-1-ol 53 mg, 38% yield as apale-yellow solid. LCMS m/z = 296, 297 [M+H]⁺ 576-chloro-1-(((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: ((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methanol 793mg, 87% as a viscous oil. LCMS m/z = 281 [M+H]⁺

Preparations 58-61

The compounds in the following table were prepared from6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine and the appropriate alcohol,following a similar procedure to that described in Preparation 36.

Preparation Number Name/Structure/Alcohol/Data 58(S)-6-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-3-iodo-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol 1.08 g, 70.9% yield, asa white solid, LCMS m/z = 405 [M+H]⁺ 59(S)-6-chloro-3-iodo-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol 602 mg, 86% yield,as an off-white solid, LCMS m/z = 393 [M+H]⁺ 60(S)-6-chloro-3-iodo-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(pyridin-3-yl)ethan-1-ol 583 mg, 56.5% yield, as anoff-white solid. 616-chloro-3-iodo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (tetrahydro-2H-pyran-4yl)methanol 1.03 g, 76% yield as whitecrystalline solid.

Preparation 62.(S)-3,6-dichloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

A mixture of 3,6-dichloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.587mmol), (R)-1-(pyridin-3-ylethan-1-ol (215 mg, 1.746 mmol) and PPh₃ (500mg, 1.905 mmol) in THF (8 mL) was cooled in an ice bath. DIAD (385 mg,1.905 mmol) was added dropwise and the reaction allowed to warm slowlyto rt. The mixture was concentrated in vacuo, the residue pre-loadedonto silica gel and purified by Isco chromatography (0 to 40%EtOAc/Hex). The product was further purified by Isco (0-60% EtOAc/DCM)to give the title compound, as an off-white solid, 230 mg. LCMS m/z =296 [M+H]⁺.

Preparation 63.(S)-3,6-dichloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-blpyrazine

A mixture of 3,6-dichloro-1H-pyrazolo[3,4-b]pyrazine (213 mg, 1.127mmol), (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (175 mg, 1.24 mmol) andPPh₃ (355 mg, 1.352 mmol) in THF (8 mL) was cooled in an ice bath. DIAD(273 mg, 1.352 mmol) was added dropwise and the reaction allowed to warmslowly to rt. The mixture was concentrated in vacuo and the residuepre-loaded onto silica gel and purified by Isco chromatography (0 to 40%EtOAc/Hex) to give the title compound as a white solid, 182 mg. LCMS m/z= 314 [M+H]⁺.

Preparation 64.4-((6-chloro-1H-pyrazolor3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol),4-(hydroxymethyl)pyrrolidin-2-one (246 mg, 2.135 mmol) and PPh₃ (611 mg,2.329 mmol) in THF (10 mL) was added DIAD (471 mg, 2.329 mmol) drop wiseat 0° C., and the reaction allowed to warm to rt. The reaction wasconcentrated in vacuo and the residue was purified by columnchromatography on silica gel eluting with MeOH/DCM (0 to 5%) to give thetitle compound (152 mg) as an off-white solid. LCMS m/z = 252 [M+H]⁺.

Preparation 65.6-chloro-1-(1,4-dioxaspiro[4.5ldecan-8-yl)-1H-pyrazolo[3,4-b]pyrazine

A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol),1,4-dioxaspiro[4.5]decan-8-ol (368 mg, 2.34 mmol) and PPh₃ (611 mg, 2.34mmol) in THF (8 mL) was cooled in an ice bath. DIAD (471 mg, 2.34 mmol)was added dropwise and the reaction allowed to warm slowly to rt. Themixture was concentrated in vacuo and the residue pre-loaded onto silicagel and purified by Isco chromatography (0 to 50% EtOAc/Hex) to give thetitle compound, as a colorless oil, 324 mg that crystallised onstanding. LCMS m/z = 295 [M+H]⁺.

Preparation 66.4-(6-chloro-1H-pyrazolo[3,4-blpyrazin-1-yl)cyclohexan-1-one

1 M HCl (2.75 mL) was added to a solution of6-chloro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 65, 270 mg, 0.92 mmol) in THF (3 mL) and the solutionstirred at rt overnight. The reaction was heated to 60° C. for 1 h, thencooled to rt. The mixture was concentrated in vacuo and the residueneutralised using aq. NaHCO₃. The resulting suspension was filtered,washed with water and dried to afford the title compound, 194 mg, 77.3%,as a white solid. LCMS m/z = 251 [M+H]⁺.

Preparation 67.(1r,4r)-4-(6-chloro-1H-pyrazolo[3,4-blpyrazin-1-yl)cyclohexan-1-ol

NaBH₄ (36 mg, 0.957 mmol) was added to a ice cooled solution of4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-one (Preparation66, 160 mg, 0.638 mmol) in MeOH (4 mL) and the reaction stirred for 1 h.The mixture was concentrated in vacuo and saturated aq. NH₄Cl solutionand then water were added. The resulting suspension was stirred forseveral minutes and then filtered, washed with water and suction driedto give a white solid, 130 mg. This was recrystallised from MeCN toprovide the title compound, 90 mg as white needles. LCMS m/z = 253[M+H]⁺.

Preparation 68.3,6-dichloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

NCS (221 mg, 1.654 mmol) and HBF₄ (218 mg, 2.481 mmol) were added to asolution of6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 87, 209 mg, 0.827 mmol) in MeCN (2 mL) and the reactionheated at 90° C. overnight. The cooled mixture was concentrated invacuo, the resulting slurry neutralized with 1M NaOH (150 µL), dilutedwith water and extracted with EtOAc. The combined organic layer waswashed with brine, dried over Na₂SO₄, filtered and evaporated to givethe crude product. This was purified by Isco chromatography (0 to 25%EtOAc/Hex) to give the title compound, 135 mg, 56.8%, of white solid.LCMS m/z = 289 [M+H]⁺.

Preparation 69.6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile

CuCN (54 mg, 0.607 mmol) was added to a solution of6-chloro-3-iodo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 61, 209 mg, 0.552 mmol) in DMSO (1.5 mL) and the reactionheated at 150° C. for 1.5 h. The cooled mixture was diluted with waterand extracted with EtOAc. The biphasic mixture was filtered throughCelite® and the filtrate separated. The organic layer was washed withwater, then brine, dried over Na₂SO₄, filtered and evaporated underreduced pressure. The crude product was purified by Isco chromatography(0 to 40% EtOAc/Hex) to give the title compound, 62 mg, 40.4%, as awhite solid. LCMS m/z = 278 [M+H]⁺.

Preparation 70.(S)-6-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile

The title compound was obtained as a white solid, 105 mg, 46.7% yield,from(S)-6-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-3-iodo-1H-pyrazolo[3,4-b]pyrazine(Preparation 58), following the procedure described in Preparation 69.LCMS m/z = 303 [M+H]⁺.

Preparation 71.(S)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile

The title compound was obtained as a white solid, 170 mg, 37.9% yield,from(S)-6-chloro-3-iodo-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 59), following the procedure described in Preparation 69.LCMS m/z = 292 [M+H]⁺.

Preparation 72.1-(6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one

A mixture of6-chloro-3-iodo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 61, 1.0 g, 2.64 mmol), tributyl(1-ethoxyvinyl)stannane(1.002 g, 2.77 mmol) and Pd(PPh₃)Cl₂ (93 mg, 0.132 mmol) in dioxane (10mL) was stirred at 90° C. overnight. The reaction was cooled to 60° C.,1 M HCl (2.6 mL) added and the mixture stirred for 45 mins. The mixturewas cooled to rt, 1 M NaOH (2.6 mL) added, the mixture diluted withEtOAc and the layers separated. The organic layer was washed with brine,dried over Na₂SO₄, filtered and evaporated under reduced pressure. Thecrude product was purified by Isco chromatography (0 to 100% EtOAc/Hex)to give the title compound, 697 mg, 90% yield, as a pale yellowcrystalline solid. LCMS m/z = 295 [M+H]⁺.

Preparation 73.(S)-1-(6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one

The title compound was obtained as an off-white solid, 634 mg, 80%yield, from(S)-6-chloro-3-iodo-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 59), following the procedure described in Preparation 72.LCMS m/z = 309 [M+H]⁺.

Preparation 74.(S)-1-(6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one

The title compound was obtained as a pale yellow crystalline solid, 697mg, 88% yield, from(S)-6-chloro-3-iodo-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 60), following the procedure described in Preparation 72.LCMS m/z = 302 [M+H]⁺.

Preparation 75.1-(6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol

NaBH₄ (45 mg, 1.194 mmol) was added to a solution of1-(6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one(Preparation 72, 352 mg, 1.194 mmol) in MeOH (7 mL) at -40° C. and thereaction allowed to warm slowly to rt. Sat. aq. NH₄Cl and water wereadded and the mixture concentrated in vacuo. The resulting aqueousslurry was partitioned between water and DCM, the layers separated andthe organic layer dried (Na₂SO₄), filtered and concentrated in vacuo.The crude product was purified by Isco chromatography (0 to 100%EtOAc/Hex) to give the title compound, 217 mg, 61.2% as an off-whitesolid. LCMS m/z = 297 [M+H]⁺.

Preparation 76.1-(6-chloro-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol

The title compound was obtained as a colorless viscous oil, 412 mg, 81%yield, from(S)-1-(6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one(Preparation 73), following a similar procdure to that described inPreparation 75.

Preparation 77.1-(6-chloro-1-((S)-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol

NaBH₄ (45 mg, 1.18 mmol) was added to a solution of(S)-1-(6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one(Preparation 74, 297 mg, 0.98 mmol) dissolved in MeOH (5 mL) and cooledin an ice bath and the reaction stirred for 20 mins. The reaction wasquenched with aq. sat. NH₄Cl, then water and the mixture extracted withDCM. The combined organic extracts were dried (Na₂SO₄), filtered andevaporated under reduced pressure. The crude product was purified byIsco chromatography (0 to 5% MeOH/DCM) to give the title compound, 103mg, 34.4%, as tan-colored foam. LCMS m/z = 304 [M+H]⁺.

Preparation 78.4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydro-2H-pyran-4-ol

A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (175 mg, 1.132 mmol),1,6-dioxaspiro[2.5]octane (155 mg, 1.359 mmol) and K₂CO₃ (313 mg, 2.265mmol) in MeCN (3 mL) was heated at 90° C. for 2 days. The cooled mixturewas diluted with EtOAc, filtered and the filtrate evaporated underreduced pressure to give the crude product. This was purified by Iscochromatography (0 to 100% EtOAc/Hex) to give4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydro-2H-pyran-4-ol,33 mg of colorless oil that crystallized on standing and4-((6-chloro-2H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydro-2H-pyran-4-ol,36 mg of colorless oil that crystallized on standing. NOE analysis,confirmed the structural assignments. LCMS m/z = 269, 270 [M+H]⁺.

Preparation 79.6-chloro-1-(2-cyclopropylpropan-2-yl)-1H-pyrazolo[3,4-b]pyrazine

To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (1.35 g, 8.78 mmol)and 2-cyclopropylpropan-2-ol (440 mg, 4.39 mmol) in DCM (30 ml) wasadded trifluoromethanesulfonic acid (658 mg, 4.39 mmol) dropwise at 0°C. and the reaction stirred at 0° C. for 30 min. The reaction mixturewas quenched with saturated aq. NaHCO₃ and extracted with EtOAc. Theorganic layer was concentrated in vacuo and the residue was purified bysilica gel chromatography eluting with PE/EtOAc (9/1) to give the titlecompound (320 mg, 31 % yield) as a colorless oil. ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.69 (s, 1H), 8.48 (s, 1H), 1.69 (s, 6H), 1.65-1.58 (m,1H), 0.42-0.40 (m, 4H).

Preparation 80.6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (200 mg, 1.29 mmol),tetrahydro-2H-pyran-4-ol (197 mg, 1.93 mmol) and PPh₃ (506 mg, 1.93mmol) in THF (10 mL) was added DIAD (390 mg, 1.93 mmol) drop wise at 0°C., and the reaction stirred at rt overnight under N₂. The reaction wasquenched with water and extracted with EtOAc. The combined organic layerwas washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with EtOAc/PE (¼) to give the title compound (150mg, 49% yield) as a yellow solid. LCMS m/z = 239 [M+H]⁺.

Preparation 81.(S)-6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (1.0 g, 6.46 mmol),(R)-1-(pyridin-3-yl)ethan-1-ol (1.19 g, 9.69 mmol) and PPh₃ (2.54 g,9.69 mmol) in THF (30 mL) was added dropwise DIAD (1.95 g, 9.69 mmol) at0° C. and the reaction stirred overnight. The reaction was quenched withwater and extracted with EtOAc. The combined organic layer was washedwith water and brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash chromatography on silica geleluting with EtOAc/PE (¼) to afford the title compound (1.5 g, 89 %yield) as a yellow solid. LCMS m/z = 260 [M+H]⁺.

Preparation 82.(S)-6-chloro-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (900 mg, 5.82 mmol),(R)-1-(pyridin-2-yl)ethan-1-ol (859 mg, 6.98 mmol) and PPh₃ (2.28 g,8.73 mmol) in THF (20 mL) was added dropwise DIAD (1.76 g, 8.73 mmol) at0° C. and the reaction stirred at rt overnight. The reaction wasquenched with water and extracted with EtOAc. The combined organic layerwas washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with EtOAc/PE (⅕) to give the title compound (900mg, 59% yield) as a yellow solid. LCMS m/z = 260 [M+H]⁺.

Preparation 83.6-chloro-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (200 mg, 1.29 mmol),1-(4-fluoropyridin-2-yl)ethanol (200 mg, 1.40 mmol) and PPh₃ (510 mg,1.94 mmol) in THF (10 mL) was added dropwise DIAD (254 mg, 1.94 mmol) at0° C. and the reaction stirred overnight. The reaction was quenched withwater and extracted with EtOAc. The combined organic layer was washedwith water and brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash chromatography on silica geleluting with EtOAc/PE (⅒) to afford the title compound (120 mg, 29%yield) as a yellow solid. LCMS m/z = 278 [M+H]⁺.

Preparation 84.6-chloro-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 2-fluoro-1-(pyridin-2-yl)ethan-1-ol (Preparation 15, 400mg, 2.83 mmol), 6-chloro-1H-pyrazolo[3,4-b]pyrazine (437 mg, 2.83 mmol)and PPh₃ (1.11 g, 4.24 mmol) in THF (10 mL) was added DIAD (857 mg, 4.24mmol) slowly, and the reaction stirred at rt for 15 h. The reaction wasquenched with water and extracted with EtOAc. The combined organic layerwas washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with EtOAc/PE (1/1) to afford the title compound(400 mg, 51%) as a colorless oil. LCMS m/z = 278 [M+H]⁺.

Preparation 85.6-chloro-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixiture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (120 mg, 0.776mmol), 2-fluoro-1-(pyridin-3-yl)ethan-1-ol (Preparation 16, 109 mg,0.776 mmol) and PPh₃ (304 mg, 1.16 mmol) in toluene (5 mL) was addedDIAD (234 mg, 1.16 mmol) and the reaction stirred at 80° C. for 2 h. Thereaction was quenched with water and extracted with EtOAc. The combinedorganic layer was washed with water and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with EtOAc/PE (2/1) to afford thetitle compound (180 mg, 84% yield) as a colorless oil. LCMS m/z = 278[M+H]⁺.

Preparation 86.6-chloro-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (850 mg, 5.49 mmol),1-(pyridazin-3-yl)ethan-1-ol (681 mg, 5.49 mmol) and PPh₃ (2.15 g, 8.23mmol) in THF (10 mL) was added DIAD (1.66 g, 8.23 mmol) dropwise at 0°C. and the reaction stirred at 25° C. for 18 h. The reaction wasquenched with water and extracted with EtOAc. The combined organic layerwas washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with EtOAc/PE (¼) to afford the title compound(550 mg, 38% yield) as a yellow solid. LCMS m/z = 261, 263 [M+H]⁺.

Preparation 87.6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (1.0 g, 6.5 mmol),(tetrahydro-2H-pyran-4-yl)methanol (1.13 g, 9.75 mmol) and PPh₃ (2.56 g,9.75 mmol) in THF (30 mL) was added DIAD (1.96 g, 9.75 mmol) at 0° C.,and the reaction stirred overnight at rt under N₂. The reaction wasquenched with water and extracted with EtOAc. The combined organiclayers were washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with EtOAc/PE (⅓) to afford the title compound(1.57 g, 95% yield) as a white solid. LCMS m/z = 253 [M+H]+.

Preparation 88.6-chloro-1-(1-(tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (200 mg, 3.34 mmol),1-(tetrahydrofuran-3-yl)ethanol (400 mg, 3.40 mmol) and PPh₃ (1.02 g,3.88 mmol) in THF (10 mL) was added DIAD (508 mg, 3.88 mmol) drop wiseat 0° C., and the reaction stirred at rt overnight. The reaction wasquenched with water and extracted with EtOAc. The combined organic layerwas washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with EtOAc/PE (⅒) to afford the title compound(240 mg, 29% yield) as a yellow solid. LCMS m/z = 253 [M+H]⁺.

Preparation 89.6-chloro-1-(1-(tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol),PPh₃ (760 mg, 2.90 mmol) and 1-(tetrahydro-2H-pyran-3-yl)ethan-1-ol(Preparation 12, 377 mg, 2.90 mmol) in THF (8 mL) was added DIAD (586mg, 2.90 mmol) at 0° C., and the reaction stirred overnight. Thereaction was quenched with water and extracted with EtOAc. The combinedorganic layer was washed with water and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with EtOAc/PE (¼) to give the titlecompound (323 mg, 62% yield) as a yellow oil. LCMS m/z = 267 [M+H]⁺.

Preparation 90.(S)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (250 mg, 1.62 mmol),(R)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol (200 mg, 1.70 mmol) and PPh₃(636 mg, 2.43 mmol) in THF (10 mL) was added dropwise DIAD (422 mg, 2.43mmol) at 0° C. and the reaction stirred overnight. The reaction wasquenched with water and extracted with EtOAc. The combined organic layerwas washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with EtOAc/PE (⅒) to afford the title compound (80mg, 19% yield) as a yellow solid. LCMS m/z = 267 [M+H]⁺.

Preparation 91.(R)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of(S)-1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethan-1-ol(Preparation 10, 700 mg, 2.31 mmol), 6-chloro-1H-pyrazolo[3,4-b]pyrazine(357 mg, 2.31 mmol) and PPh₃ (907 mg, 3.46 mmol) in toluene (5 mL) wasadded DIAD (699 mg, 3.46 mmol) at 0° C. and the reaction stirred at 80°C. for 4 h. The reaction was quenched with water and extracted withEtOAc. The combined organic layer was washed with water and brine, driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel eluting with EtOAc/PE(1/1) to give the title compound (700 mg, 69% yield) as a yellow oil.LCMS m/z = 439 [M+H]⁺.

Preparation 92.6-chloro-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (400 mg, 2.59 mmol),(2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol (Preparation 6, 730mg, 3.88 mmol) and PPh₃ (784 mg, 3.88 mmol) in THF (10 mL) was addeddropwise DIAD (1.02 g, 3.88 mmol) at 0° C., and the reaction thenstirred overnight. The reaction was quenched with water and extractedwith EtOAc. The combined organic layer was washed with water and brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel eluting with EtOAc/PE (⅒)to give the title compound (180 mg, 21% yield) as a yellow solid. LCMSm/z = 241 [M-84+H]⁺.

Preparation 93.6-chloro-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

To a mixture of 2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol(Preparation 11, 200 mg, 1.20 mmol), tetrahydro-2H-pyran-4-ol (185 mg,1.20 mmol) and PPh₃ (471 mg, 1.8 mmol) in THF (10 mL) was added dropwiseDIAD (363 mg, 1.8 mmol) at 0° C., and the reaction stirred overnight.The reaction was quenched with water and extracted with EtOAc. Thecombined organic layer was washed with water and brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with EtOAc/PE (¼) to give thetitle compound (250 mg, 69% yield) as a yellow solid. LCMS m/z = 303[M+H]⁺.

Preparation 94.Trans-rac-2-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile

Trans-racemate

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (794 mg, 5.14 mmol),trans-2-(hydroxymethyl)cyclopropane-1-carbonitrile (500 mg, 5.14 mmol)and PPh₃ (1.61 g, 6.16 mmol) in toluene (10 mL) was added dropwise DIAD(1.24 g, 6.16 mmol) at 0° C., and the reaction stirred at 80° C.overnight. The reaction was quenched with water, extracted with EtOAc,the combined organic layer was washed with water and brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with EtOAc/PE (¼) to give thetitle compound (400 mg, 33% yield) as a white solid. LCMS m/z = 234[M+H]⁺.

Preparation 95-182

To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine,6-chloro-3-methyl-1H-pyrazolo[3,4-b]pyrazine or6-chloro-3-fluoro-1H-pyrazolo[3,4-b]pyrazine (Preparation 3) (1 equiv.)as indicated in the table, the appropriate alcohol (1.0 to 3.0 equiv.)and PPh₃ (1.5 to 2.0 equiv.) in THF was added DIAD (1.5 to 2.0 equiv.)drop wise at 0° C., and the reaction stirred at rt until the startingmaterials had been consumed. The reaction was quenched with water,extracted with EtOAc, the combined organic layer was washed with waterand brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withEtOAc/PE to give the title compounds.

Preparation Number Name/Structure/Alcohol/Data Using6-chloro-1H-pyrazolo[3,4-b]pyrazine 95 methyl(R)-3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate

Alcohol: methyl (R)-3-hydroxy-2-methylpropanoate 200 mg, 40% yield as awhite solid. LCMS m/z = 255, 257 [M+H]⁺ 966-chloro-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (tetrahydro-2H-pyran-3-yl)methanol 1.2 g, 92% yield as a whitesolid. LCMS m/z = 253 [M+H]⁺ 97^(A)(S)-6-chloro-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (S)-(tetrahydro-2H-pyran-3-yl)methanol 501 mg, 88% yield as ayellow solid. LCMS m/z = 253 [M+H]⁺ 98(R)-6-chloro-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-(tetrahydro-2H-pyran-3-yl)methanol 320 mg, 65% yield as asolid. LCMS m/z = 253 [M+H]⁺ 996-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (tetrahydrofuran-3-yl)methanol 1.0 g, 80% yield as a whitesolid. LCMS m/z = 239 [M+H]⁺ 1006-chloro-1-((3-methyltetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (3-methyltetrahydrofuran-3-yl)methanol 300 mg, 61% yield as awhite solid. LCMS m/z = 253 [M+H]⁺ 1016-chloro-1-((3-fluorotetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (3-fluorotetrahydrofuran-3-yl)methanol 150 mg, 42% yield as awhite solid. LCMS m/z = 271 [M+H]⁺ 1023-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydrofuran-3-carbonitrile

Alcohol: 3-(hydroxymethyl)oxolane-3-carbonitrile 200 mg, 78% yield as awhite solid. LCMS m/z = 264 [M+H]⁺ 103(R)-6-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-(tetrahydrofuran-2-yl)methanol 200 mg, 86% yield as ayellow solid. LCMS m/z = 239 [M+H]⁺ 104 tert-butyl(S)-3-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate

Alcohol: tert-butyl (S)-3-(hydroxymethyl)piperidine-1-carboxylate 300mg, 52% yield, as a yellow solid. LCMS m/z = 352 [M+H]⁺ 105 methyl(S)-3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate

Alcohol: methyl (S)-3-hydroxy-2-methylpropanoate 100 mg, 24% yield as ayellow solid. LCMS m/z = 255 [M+H]⁺ 106(R)-6-chloro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (S)-tetrahydro-2H-pyran-3-ol 80 mg, 51 % yield as white solid.LCMS m/z = 239 [M+H]⁺ 1071-(tert-butyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 2-methylpropan-2-ol 126 mg, 60% yield as a yellow solid. LCMSm/z = 211 [M+H]⁺ 1086-chloro-1-(cyclopropylmethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: cyclopropylmethanol 100 mg, 74% yield as a white solid. LCMSm/z = 209 [M+H]⁺ 109^(A)1-((3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (3-oxabicyclo[3.1.0]hexan-6-yl)methanol 200 mg, 41% yield as awhite solid. LCMS m/z = 251 [M+H]⁺ 1101-(((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: ((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)methanol 270 mg, 84%yield as a yellow solid. LCMS m/z = 251 [M+H]⁺ 1111-(((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: ((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)methanol 280 mg, 57%yield as a yellow oil. LCMS m/z = 251 [M+H]⁺ 1126-chloro-1-((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol (Preparation7) 90 mg, 42% yield as a yellow solid. LCMS m/z = 241 [M+H]⁺ 113(R)-6-chloro-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (S)-1-(pyridin-2-yl)ethan-1-ol 200 mg, 59% yield as a yellowsolid. LCMS m/z = 260 [M+H]⁺ 1146-chloro-1-(oxetan-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (oxetan-3-yl)methanol 110 mg, 75% yield as a white solid. LCMSm/z = 225 [M+H]⁺ 1156-chloro-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (3-methyloxetan-3-yl)methanol 180 mg, 77% yield as a whitesolid. LCMS m/z = 239 [M+H]⁺ 116(S)-6-chloro-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (S)-(tetrahydro-2H-pyran-2-yl)methanol 220 mg, 67% yield as ayellow solid. LCMS m/z = 253 [M+H]⁺ 117(R)-6-chloro-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-(tetrahydro-2H-pyran-2-yl)methanol 300 mg, 92% yield as ayellow solid. LCMS m/z = 253 [M+H]⁺ 118(S)-1-((1,4-dioxan-2-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (S)-(1,4-dioxan-2-yl)methanol 80 mg, 19% yield as a yellowsolid. LCMS m/z = 255 [M+H]⁺ 119(R)-1-((1,4-dioxan-2-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-(1,4-dioxan-2-yl)methanol 80 mg, 19% yield as a yellow oil.LCMS m/z = 255 [M+H]⁺ 1206-chloro-1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (4-methyltetrahydro-2H-pyran-4-yl)methanol 200 mg, 25% yield asa white solid. LCMS m/z = 267 [M+H]⁺ 1216-chloro-1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (4-fluorotetrahydro-2H-pyran-4-yl)methanol 150 mg, 42% yield asa white solid. LCMS m/z = 271 [M+H]⁺ 1224-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydro-2H-pyran-4-carbonitrile

Alcohol: 4-(hydroxymethyl)tetrahydro-2H-pyran-4-carbonitrile 400 mg, 89%yield as a white solid. LCMS m/z = 278 [M+H]⁺ 123^(A)6-chloro-1-((4-(trifluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (4-(trifluoromethyl)tetrahydro2H-pyran-4-yl)methanol 60 mg, 28%yield as a white solid. LCMS m/z = 321 [M+H]⁺ 124^(A)6-chloro-1-((4-(difluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (4-(difluoromethyl)tetrahydro2H-pyran-4-yl)methanol 300 mg, 36%yield as a white solid. LCMS m/z = 303 [M+H]⁺ 1256-chloro-1-(cyclopropyl(tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: cyclopropyl(tetrahydro-2H-pyran-4-yl)methanol 180 mg, 64% yieldas a yellow solid. LCMS m/z = 293 [M+H]⁺ 1261-((8-oxabicyclo[3.2.1]octan-3-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (8-oxabicyclo[3.2.1]octan-3-yl)methanol 246 mg, 57% yield as ayellow solid. LCMS m/z = 279 [M+H]⁺ 1271-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (2-oxabicyclo[2.2.2]octan-4-yl)methanol 150 mg, 83% yield as awhite solid. LCMS m/z = 279 [M+H]⁺ 128(R)-6-chloro-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazine or(S)-6-chloro-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: Enantiomer 1 (Preparation 20 and 21) 150 mg, 54% yield as ayellow oil. LCMS m/z = 277 [M+H]⁺ 129(S)-6-chloro-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazine or(R)-6-chloro-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: Enantiomer 2 (Preparation 20 and 21) 150 mg, 54% yield as ayellow oil. LCMS m/z = 277 [M+H]⁺ 130(R)-6-chloro-1-(1-phenyl-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (S)-1-phenyl-2-((triisopropylsilyl)oxy)ethan-1-ol (Preparation23) 700 mg, 53% yield as a yellow solid. 131(R)-6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (S)-1-(pyridin-3-yl)ethan-1-ol 200 mg, 59% yield as a whitesolid. LCMS m/z = 260 [M+H]⁺ 1323-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol

Alcohol: cyclopentane-1,3-diol 200 mg, 43% yield as a white solid. LCMSm/z = 239 [M+H]⁺ 133(S)-6-chloro-1-(1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-phenylethan-1-ol 550 mg, 66% yield. LCMS m/z = 259 [M+H]⁺134 6-chloro-1-(oxetan-3-yl(phenyl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: oxetan-3-yl(phenyl)methanol (Preparation 22) 300 mg, 30% yield.LCMS m/z = 301 [M+H]⁺ 135(S)-6-chloro-1-(1-(pyridin-3-yl)propyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(pyridin-3-yl)propan-1-ol 120 mg, 44% yield as a yellowoil. LCMS m/z = 274 [M+H]⁺ 136(S)-6-chloro-1-(1-(pyridin-2-yl)propyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(pyridin-2-yl)propan-1-ol 200 mg, 56% yield as a yellowoil. LCMS m/z = 274 [M+H]⁺ 137^(A)(R)-6-chloro-1-(1-(pyridin-3-yl)-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (S)-1-(pyridin-3-yl)-2-((triisopropylsilyl)oxy)ethan-1-ol(Preparation 26) 600 mg, 59% yield as a yellow oil. LCMS m/z = 432[M+H]⁺ 138 3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutan-1-ol

Alcohol: cyclobutane-1,3-diol 135 mg, 47% yield as a white solid. LCMSm/z = 225 [M+H]⁺ 1396-chloro-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (2-methylpyridin-3-yl)methanol 300 mg, 71% yield as a yellowsolid. LCMS m/z = 260 [M+H]⁺ 1406-chloro-1-((4-methylpyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (4-methylpyridin-3-yl)methanol 260 mg, 77% yield as a yellowsolid. LCMS m/z = 260 [M+H]⁺ 1416-chloro-1-(cyclopropyl(pyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: cyclopropyl(pyridin-3-yl)methanol 250 mg, 47% yield as a yellowoil. LCMS mz = 286 [M+H]⁺ 142(S)-6-chloro-1-(cyclopropyl(pyridin-2-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-cyclopropyl(pyridin-2-yl)methanol hydrochloride 50 mg, 16%yield as a yellow oil. LCMS mz = 286 [M+H]⁺ 1436-chloro-1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 1-(6-fluoropyridin-3-yl)ethan-1-ol 450 mg, 83% yield as a whitesolid. LCMS mz = 278 [M+H]⁺ 1446-chloro-1-(1-(5-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 1-(5-fluoropyridin-3-yl)ethan-1-ol 120 mg, 55% yield as ayellow solid. LCMS mz = 278 [M+H]⁺ 1456-chloro-1-(1-(6-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 1-(6-fluoropyridin-2-yl)ethan-1-ol 560 mg, 78% yield as ayellow solid. LCMS mz = 278 [M+H]⁺ 1466-chloro-1-(1-(4-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 1-(4-fluoropyridin-3-yl)ethan-1-ol (Preparation 18) 70 mg, 36%yield as a yellow solid. LCMS mz = 278 [M+H]⁺ 1476-chloro-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 1-(4-fluoropyridin-2-yl)ethan-1-ol (Preparation 19) 210 mg, 53%yield as a yellow solid. LCMS mz = 278 [M+H]⁺ 1486-chloro-1-(1-(4-chloropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 1-(4-chloropyridin-2-yl)ethan-1-ol 320 mg, 37% yield. LCMS m/z= 294 [M+H]⁺ 1496-chloro-1-((1-methylcyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (1-methylcyclopropyl)methanol 130 mg, 90% yield as a yellowoil. LCMS m/z = 223 [M+H]⁺ 1506-chloro-1-isobutyl-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 2-methylpropan-1-ol 150 mg, 55% yield. LCMS m/z = 211 [M+H]⁺151 6-chloro-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: cyclobutylmethanol 150 mg, 52% yield. LCMS m/z = 223 [M+H]⁺ 1526-chloro-1-(cyclopentylmethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: cyclopentylmethanol 170 mg, 56% yield. LCMS m/z = 237 [M+H]⁺153 6-chloro-1-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: cyclohexylmethanol 160 mg, 50% yield. LCMS m/z = 251 [M+H]⁺ 1541-(bicyclo[1.1.1]pentan-1-ylmethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: bicyclo[1.1.1]pentan-1-ylmethanol 180 mg, 59% yield. LCMS m/z =235 [M+H]⁺ 1556-chloro-1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (3-fluorobicyclo[1.1.1]pentan-1-yl)methanol 88 mg, 53% yield asa yellow solid. LCMS m/z = 253 [M+H]⁺ 1566-chloro-1-(spiro[2.2]pentan-1-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: spiro[2.2]pentan-1-ylmethanol 520 mg, 85% yield as a colorlessoil. LCMS m/z = 235 [M+H]⁺ 1576-chloro-1-((4,4-difluorocyclohexyl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 4,4-difluorocyclohexylmethanol 120 mg, 42% yield. LCMS m/z =287 [M+H]⁺ 1584-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclohexan-1-ol

Alcohol: 4-(hydroxymethyl)cyclohexan-1-ol 600 mg, 87% yield. LCMS m/z =267 [M+H]⁺ 159Cis-Rac-6-chloro-1-((2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazine

cis-racemate Alcohol: cis-rac-(2-fluorocyclopropyl)methanol 150 mg, 61%yield. LCMS m/z = 227 [M+H]⁺ 160Trans-rac-6-chloro-1-((2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazine

trans-racemate Alcohol: trans-rac-(2-fluorocyclopropyl)methanol 490 mg,83% yield as a colorless oil. LCMS m/z = 227 [M+H]⁺ 1616-chloro-1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (2,2-difluorocyclopropyl)methanol 125 mg, 27% yield as a yellowsolid. LCMS m/z = 245 [M+H]⁺ 162^(A)6-chloro-1-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (6,6-difluorobicyclo[3.1.0]hexan-3-yl)methanol 260 mg, 91%yield as a white solid. LCMS m/z = 285 [M+H]⁺ 163^(A)1-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutan-1-ol

Alcohol: 1-(hydroxymethyl)cyclobutan-1-ol 180 mg, 75% as a white solid.LCMS m/z = 239 [M+H]⁺ 1646-chloro-1-((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol:(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methanol(Preparation 27) 80 mg, 23% as a yellow solid. LCMS m/z = 335 [M+H]⁺165^(A)6-chloro-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 2-fluoro-1-(oxan-4-yl)ethan-1-ol 900 mg, 59% as a yellow oil.LCMS m/z = 285 [M+H]⁺ 166^(A)3-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)-5,5-dimethylpyrrolidin-2-one

Alcohol: 3-(hydroxymethyl)-5,5-dimethylpyrrolidin-2-one (Preparation 29)300 mg, 38% as a yellow solid. LCMS m/z = 280 [M+H]⁺ 1676-chloro-1-(4-((triisopropylsilyl)oxy)butan-2-yl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 4-((triisopropylsilyl)oxy)butan-2-ol (Preparation 24) 300 mg,39% yield as a white solid. LCMS m/z = 383 [M+H]⁺ 168(S)-6-chloro-1-(1-(oxetan-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(oxetan-3-yl)ethan-1-ol 320 mg, 77% as a yellow oil. LCMSm/z = 239 [M+H]⁺ 1691-((1H-indazol-4-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (1H-indazol-4-yl)methanol 150 mg, 39% as a yellow solid. LCMSm/z = 285 [M+H]⁺ 1701-(2-(1H-pyrazol-4-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 2-(1H-pyrazol-4-yl)ethan-1-ol 300 mg, 97% as a yellow solid.LCMS m/z = 249 [M+H]⁺ 171^(A)6-chloro-1-(2-(pyridin-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 2-(pyridin-4-yl)ethan-1-ol 300 mg, 71% as a yellow oil. LCMSm/z = 260 [M+H]⁺ 172^(A)6-chloro-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (1-methyl-1H-imidazol-5-yl)methanol 257 mg, 58% as a yellowoil. LCMS m/z = 249 [M+H]⁺ 1735-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)isoxazole

Alcohol: (isoxazol-5-yl)methanol 65 mg, 21%. LCMS m/z = 236 [M+H]⁺174^(A)2-(1-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropyl)acetonitrile

Alcohol: 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile 90 mg, 14% as asolid. LCMS m/z = 248 [M+H]⁺ 175^(A)3-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutane-1-carbonitrile

Alcohol: 3-(hydroxymethyl)cyclobutane-1-carbonitrile 280 mg, 84% as ayellow oil. LCMS m/z = 248 [M+H]⁺ 176^(A)1-(3-((benzyloxy)methyl)cyclobutyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Alcohol: 3-((benzyloxy)methyl)cyclobutan-1-ol 460 mg, 53% as a yellowsolid. LCMS m/z = 329 [M+H]⁺ 177^(A)1-(((1r,3r)-3-(benzyloxy)cyclobutyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Alcohol: trans-3-(benzyloxy)cyclobutyl)methanol 450 mg, 58% as a yellowsolid. LCMS m/z = 329 [M+H]⁺ 1786-chloro-3-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: pyridin-3-ylmethanol 450 mg, 58% yield. LCMS m/z = 260 [M+H]⁺1796-chloro-3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (tetrahydro-2H-pyran-4-yl)methanol 580 mg, 92% yield. LCMS m/z= 267 [M+H]⁺ 1806-chloro-3-fluoro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (tetrahydro-2H-pyran-4-yl)methanol 100 mg, 64% yield. LCMS m/z= 271 [M+H]⁺ 181^(A)(S)-6-chloro-3-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (R)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol 1.38 g, 60% yield asa white solid. LCMS m/z = 285 [M+H]⁺ 182^(A)6-chloro-3-fluoro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine

Alcohol: (pyridin-3-yl)methanol 80 mg, 35% yield. LCMS m/z = 264 [M+H]⁺

A - toluene was the solvent and the reaction and stirred at 80° C. untilall starting materials had been consumed.

Preparation 183 and 184.Trans-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-blpyrazineandcis-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

Trans-racemate and Cis-racemate

DEAD (783 mg, 4.5 mmol) was added dropwise to an ice cooled solution of6-chloro-1H-pyrazolo[3,4-b]pyrazine (540 mg, 3.5 mmol),1-(1,4-dioxan-2-yl)ethan-1-ol (400 mg, 3.0 mmol) and PPh₃ (917 mg, 3.5mmol) in THF (10 mL) and the reaction stirred at 20° C. overnight. Thereaction was quenched with water and extracted with EtOAc. The combinedorganic layer was washed with water and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (PE:EtOAc= 4:1) to provide:

Product 1:Trans-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazineor Cis-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (90 mg, 11 % yield)

Product 2:Cis-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazineor trans-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (230 mg, 29% yield). LCMS m/z = 269,271 [M+H]⁺.

Preparation 185.2-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropan-1-ol

To a solution of6-chloro-1-((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 164, 80 mg, 0.239 mmol) in AcOH (2 mL) at 0° C. was addedH₂O₂ (30 wt%, 1 mL), and the reaction stirred at 25° C. for 18 h. Thereaction was concentrated in vacuo, and the residue was purified byflash chromatography on silica gel eluting with EtOAc/PE (⅕) to affordthe title compound (20 mg, 37% yield) as a yellow solid. LCMS m/z = 225[M+H]⁺.

Preparation 186.6-chloro-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)-1H-pyrazolo[3,4-b]pyrazine

To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (426 mg, 2.76 mmol)and 2-(oxan-4-yl)propan-2-ol (200 mg, 1.38 mmol) in DCM (15 mL) wasadded trifluoromethanesulfonic acid (621 mg, 4.14 mmol) dropwise at 0°C. and the reaction stirred at 0° C. for 30 min. The reaction mixturewas quenched with sat. aq. NaHCO₃, extracted with EtOAc and the organiclayer was concentrated in vacuo. The residue was purified by silica gelchromatography eluting with PE/EtOAc (10/1) to give the title compound(70 mg, 18% yield) as a white solid. LCMS m/z = 281 [M+H]⁺.

Preparation 187.N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of6-chloro-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 92, 180 mg, 0.554 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (124 mg, 0.831 mmol), BrettPhosPd G₄ (19.5 mg, 20 µmol) and KOAc (163 mg, 1.66 mmol) in dioxane (5.0mL) was stirred at 90° C. overnight under N₂. The reaction mixture wascooled to rt and concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with EtOAc/PE (1/1) to givethe title compound (90 mg, 37% yield) as a yellow oil. LCMS m/z = 438[M+H]⁺.

Preparation 188.N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

The title compound was obtained, 80 mg, 66% yield from6-chloro-1-((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 112) and 5-(difluoromethoxy)-1H-pyrazol-3-amine, followingthe procedure descibed in Preparation 187. LCMS m/z = 438 [M+H]⁺.

Preparation 189. Methyl(S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate

The title compound was obtained as a yellow oil, 70 mg, 48% yield, frommethyl(S)-3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate(Preparation 105) and 5-(difluoromethoxy)-1H-pyrazol-3-amine, followingthe procedure described in Preparation 187. LCMS m/z = 368 [M+H]⁺.

Preparation 190.(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of(R)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 91, 600 mg, 1.36 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (243 mg, 1.63 mmol), KOAc (400mg, 4.08 mmol) and BrettPhos Pd G4 (100 mg, 0.11 mmol) in dioxane (8 mL)was stirred at 90° C. for 2 h under N₂, The cooled reaction mixture wasconcentrated in vacuo and the residue was purified by flashchromatography on silica gel eluting with EtOAc/PE (2/1) to give thetitle compound (600 mg, 80% yield) as a yellow solid. LCMS m/z = 552[M+H]⁺.

Preparation 191.1-(((1r,3r)-3-(benzyloxy)cyclobutyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of1-((trans-3-(benzyloxy)cyclobutyl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 177, 400 mg, 1.21 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (216 mg, 1.45 mmol), t-BuXPhos PdG3 (96.6 mg, 12.1 µmol) and KOAc (355 mg, 3.62 mmol) in dioxane (10 mL)was stirred at 100° C. overnight under N₂. The cooled mixture wasconcentrated in vacuo and the residue was purified by flashchromatography on silica gel eluting with EtOAc/PE (1/1) to give thetitle compound (350 mg, 65% yield) as a yellow solid. LCMS m/z = 442[M+H]⁺.

Preparation 192.(R)-6-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

DIAD (471 mg, 2.33 mmol) was added to an ice-cold solution of6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol),R)-(tetrahydrofuran-3-yl)methanol (198 mg, 1.94 mmol) and PPh₃ (611 mg,2.33 mmol) in THF (10 mL). The resulting mixture was allowed to warmslowly and the reaction was complete when it reached 5° C. The reactionmixture was evaporated to dryness in vacuo and the residue purified byIsco chromatography (0-40% EtOAc/Hex) to afford the title compound as aviscous colourless oil (381 mg, 82%). LCMS m/z = 239 [M+H]⁺.

PREFERRED EXAMPLES Example 1(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-blpyrazin-6-amine

A mixture of(S)-6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 81, 600 mg, 2.4 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (413 mg, 2.77 mmol), Pd2(dba)3(423 mg, 0.46 mmol), tBuXPhos (196 mg, 0.46 mmol) and KOAc (453 mg, 4.62mmol) in dioxane (15 mL) was degassed with N2 (x3) and then heated at100° C. overnight under N2. The reaction mixture was cooled to rt andconcentrated to give a residue which was purified by flashchromatography (SiO2; 50% EtOAc/PE) and then by prep-HPLC-1 to affordthe title compound as a yellow solid (168 mg, 18%) as a yellow solid.LCMS m/z = 373 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ: 12.29 (s, 1H), 10.86(s, 1H), 8.59(s, 1H), 8.45 (d, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.74 (d,1H), 7.36-7.32 (m, 1H), 7.31 (t, 1H), 6.65-6.60 (m, 1H), 5.92 (s, 1H),1.92 (d, 3H).

Example 2N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 87, 780 mg, 3.09 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (554 mg, 3.72 mmol), tBuXphos PdG3 (150 mg, 0.19 mmol) and KOAc (892 mg, 9.08 mmol) in dioxane (15 mL)was stirred at 90° C. for 6 h under N₂. The reaction mixture wasevaporated to dryness in vacuo and the residue was purified byprep-HPLC-4 to afford the title compound as a white solid (361.4 mg,32%). LCMS m/z = 366 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.21 (s, 1H),10.82 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.32 (t, 1H), 5.98 (d, 1H),4.40 (d, 2H), 3.87-3.75 (m, 2H), 3.29-3.16 (m, 2H), 2.24-2.11 (m, 1H),1.46-1.29 (m, 4H).

Example 3(1r,4r)-4-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-bipyrazin-1-yl)cyclohexan-1-ol

A mixture of(1r,4r)-4-(6-chloro-1Hpyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol(Preparation 67, 45 mg, 0.178 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (29 mg, 0.196 mmol),^(t)BuBrettPhos Pd G3 (7.61 mg, 8.9 mmol) and KOAc (52 mg, 0.534 mmol)in dioxane (1 mL) was stirred at 90° C. for 1 h. The reaction mixturewas evaporated to dryness and the residue dissolved in DMSO, filteredand purified by reverse phase Isco (0 to 80% MeCN/H₂O (+ 0.1% TFA). Theappropriate fractions were treated with NaHCO₃ and extracted with 10%MeOH/DCM (4x). The combined organics were dried (Na₂SO₄) and evaporatedto dryness in vacuo to afford the title compound as a pale yellow solid(21.3 mg, 33%). LCMS m/z = 366 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ:12.22 (s, 1H), 10.72 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.31 (t, 1H),5.96 (s, 1H), 4.95-4.82 (m, 1H), 4.69 (d, 1H), 3.61-3.49 (m, 1H),2.07-1.84 (m, 6H), 1.56-1.41 (m, 2H).

Example 4(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of(S)-6-chloro-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 82, 980 mg, 3.77 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (562 mg, 3.77 mmol), t-BuXPhos PdG4 (100 mg, 0.126 mmol) and KOAc (1.10 g, 11.3 mmol) in dioxane (10 mL)was stirred at 100° C. overnight under N₂. The reaction mixture wascooled to rt, concentrated in vacuo and the residue purified by flashchromatography (SiO₂, 4:1 EtOAc/PE) followed by prep-HPLC-1 to give thetitle compound as a yellow solid (205 mg, 14%). LCMS m/z = 373 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ: 8.55 (d, 1H), 8.20 (s, 1H), 8.19 (s, 1H),7.74-7.69 (m, 1H), 7.29 (t, 1H), 7.28-7.25 (m, 1H), 7.07 (d, 1H),6.45-6.40 (m, 1H), 5.86 (s, 1H), 1.95 (d, 3H).

Example 5 and 6(2S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-bipyrazin-1-yl)pentan-2-oland(2S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol

TFA (200 mg, 2.06 mmol) was added to a mixture ofN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(Preparation 187, 90 mg, 0.205 mmol) in DCM (20 mL) at 0 oC and theresulting mixture stirred for 5 h at 25 oC. The reaction mixture wasevaporated to dryness under reduced pressure and the residue purified byprep-HPLC-1 followed by further purification by chiral-SFC (DaicelIC20x250 mm, 10 mm; 40% MeOH (+0.2% MeOH/NH3) in CO2) to afford thetitle compounds as white solids.

Peak 1, Example 5,(2S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-olor(2S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol(17.8 mg): LCMS m/z = 354 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ: 12.19 (brs, 1H), 10.90 (br s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.31 (t, 1H), 6.01(s, 1H), 5.06 (d, 1H), 4.60-4.53 (m, 1H), 4.02-3.98 (m, 1H), 2.14-1.99(m, 2H), 0.79 (d, 3H), 0.61 (t, 3H).

Peak 2, Example 6,(2S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-olor(2S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol(6.4 mg): LCMS m/z = 354 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.23 (brs, 1H), 10.92 (br s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.31 (t, 1H), 5.94(s, 1H), 4.80-4.60 (m, 2H), 4.20-4.00 (m, 1H), 2.10-1.80 (m, 2H), 1.43(d, 3H), 0.59 (t, 3H).

Example 7N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((2-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of6-chloro-1-((2-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 36, 65 mg, 0.247 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (40 mg, 0.271 mmol),^(t)BuBrettPhos Pd G3 (10.5 mg, 12 mmol) and KOAc (73 mg, 0.740 mmol) indioxane (1 mL) was stirred at 80° C. overnight. The reaction mixture wasevaporated to dryness and the residue dissolved in DMSO, filtered andpurified by reverse phase Isco (0 to 80% MeCN/H₂O (+ 0.1% TFA). Theappropriate fractions were treated with NaHCO₃ and extracted with 10%MeOH/DCM (4x). The combined organics were dried (Na₂SO₄) and evaporatedto dryness in vacuo to afford the title compound as an off-white solid(33 mg, 36%). LCMS m/z = 376 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.27(s, 1H), 10.88 (s, 1H), 8.23 (s, 1H), 8.22 (s, 1H), 8.17 (d, 1H),7.72-7.63 (m, 1H), 7.47-7.12 (m, 2H), 5.89 (s, 1H), 5.83 (s, 2H).

Example 8(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of(S)-6-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 31, 73 mg, 0.263 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (43 mg, 0.289 mmol),^(t)BuBrettPhos Pd G3 (11 mg, 13 mmol) and KOAc (77 mg, 0.789 mmol) indioxane (1 mL) was stirred at 90° C. for 1 h. The reaction mixture wasevaporated to dryness and the residue dissolved in DMSO, filtered andpurified by reverse phase Isco (0 to 80% MeCN/H₂O (+ 0.1% TFA). Theappropriate fractions were treated with NaHCO₃ and extracted with 10%MeOH/DCM (4x). The combined organics were dried (Na₂SO₄) and evaporatedto dryness in vacuo to afford the title compound as a yellow solid (26mg, 30%). LCMS m/z = 391 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.24 (s,1H), 10.82 (s, 1H), 8.23 (s, 1H), 8.22 (s, 1H), 8.16 (d, 1H), 7.91 (ddd,1H), 7.47-7.12 (m, 2H), 6.65 (q, 1H), 5.95 (d, 1H), 1.89 (d, 3H).

Example 9, 10, 11 and 12N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineandN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineandN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-blpyrazin-6-amineandN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Part 1. A mixture of6-chloro-1-(1-(tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 88, 240 mg, 0.94 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (212 mg, 1.42 mmol), BrettPhos PdG4 (40 mg, 0.42 mmol) and KOAc (280 mg, 1.42 mmol) in dioxane (5 mL) wasstirred at 90° C. overnight under N₂. The reaction mixture was cooled tort and evaporated to dryness in vacuo and the residue purified by flashchromatography on silica gel (50% EtOAc/PE) followed by prep-HPLC-1 toafford:

Intermediate Peak 1 (100 mg, 29%) and Intermediate Peak 2 (130 mg, 37%)as yellow solids.

Part 2. Intermediate Peak 1 from Part 1 was purified by Prep-SFC (DaicelOD; 20 x 250 mm, 10 mm; 40% MeOH (0.2% MeOH/NH₃) in CO₂) to afford:

Peak 1, Example 9,N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)--((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(30.5 mg); LCMS m/z = 366 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ: 12.22 (brs, 1H), 10.93 (br s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 7.31 (t, 1H), 5.95(s, 1H), 5.15-5.05 (m, 1H), 3.89-3.85 (m, 1H), 3.67-3.51 (m, 3H),2.83-2.77 (m, 1H), 2.83-2.77 (m, 1H), 1.53-1.38 (m, 5H).

Peak 2, Example 10,N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(29.6 mg); LCMS m/z = 366 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ: 12.22 (brs, 1H), 10.93 (br s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 7.31 (t, 1H), 5.95(s, 1H), 5.15-5.05 (m, 1H), 3.89-3.85 (m, 1H), 3.67-3.51 (m, 3H),2.83-2.77 (m, 1H), 2.83-2.77 (m, 1H), 1.53-1.38 (m, 5H).

Part 3. Intermediate Peak 2 from Part 1 was purified by Prep-SFC (DaicelOZ; 20 x 250 mm, 10 mm; 30% MeOH (0.2% MeOH/NH3) in CO2) to afford:

Peak 3, Example 11,N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(45.4 mg); LCMS m/z = 366 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.35-11.90 (br s, 1H), 11.05-10.65 (br s, 1H), 8.20 (s, 1H), 8.16 (s,1H), 7.30 (t, 1H), 5.97 (s, 1H), 5.08-5.03 (m, 1H), 3.80-3.75 (m, 1H),3.68-3.64 (m, 1H), 3.35-3.30 (m, 1H), 3.23-3.18 (m, 1H), 2.86-2.83 (m,1H), 2.10-2.07 (m, 1H), 1.80-1.75 (m, 1H), 1.50 (d, 3H).

Peak 4, Example 12,N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(48.1 mg); LCMS m/z = 366 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.35-11.90 (br, 1H), 11.05-10.65 (br, 1H), 8.20 (s, 1H), 8.16 (s, 1H),7.30 (t, 1H), 5.97 (s, 1H), 5.08-5.03 (m, 1H), 3.80-3.75 (m, 1H),3.68-3.64 (m, 1H), 3.35-3.30 (m, 1H), 3.23-3.18 (m, 1H), 2.86-2.83 (m,1H), 2.10-2.07 (m, 1H), 1.80-1.75 (m, 1H), 1.50 (d, 3H).

Example 13 and 14(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of6-chloro-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 147, 120 mg, 0.43 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (96 mg, 0.64 mmol), BrettPhos PdG4 (20 mg, 0.021 mmol) and KOAc (127 mg, 1.30 mmol) in dioxane (5 mL)was stirred at 90° C. overnight under N₂. The reaction mixture wascooled to rt and evaporated to dryness in vacuo. The residue waspurified by flash chromatography (SiO₂, 50% EtOAc/PE) followed byprep-HPLC-1 to affordN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineas a yellow solid (60 mg, 35%). The racemate was separated by chiralprep-SFC (Daicel OX 20 x 250 mm, 10 mm; 35% MeOH (0.2% MeOH/NH₃) in CO₂)to afford the title compounds as white solids.

Peak 1, Example 13,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(8.8 mg, 5%). LCMS m/z = 391 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ:11.80-11.40 (br s, 1H), 8.21 (s, 1H), 8.20 (s, 1H), 8.15 (d, 1H),7.92-7.86 (m, 1H), 7.35-7.32 (m, 1H), 7.33 (t, 1H), 6.62-6.59 (m, 1H),5.98 (s, 1H), 1.89 (d, 3H).

Peak 2, Example 14,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(8.3 mg, 5%). LCMS m/z = 391 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.24(s, 1H), 10.82 (s, 1H), 8.21 (s, 1H), 8.20 (s, 1H), 8.15 (d, 1H),7.92-7.86 (m, 1H), 7.35-7.32 (m, 1H), 7.33 (t, 1H), 6.62-6.59 (m, 1H),5.98 (s, 1H), 1.89 (d, 3H).

Example 15 and 16(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of6-chloro-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 84, 400 mg, 1.44 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (256 mg, 1.72 mmol), KOAc (422mg, 4.31 mmol) and BrettPhos Pd G4 (80 mg) in dioxane (5 mL) was heatedto 90° C. for 2 h. The mixture was concentrated in vacuo and the residuepurified by flash chromatography (SiO₂, 3:1 EtOAc/PE) to giveN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(100 mg, 18%) which was separated by chiral-SFC (Daicel AD-H, 20 x 250mm, 10 mm; 30% MeOH in CO2) to give:

Peak 1, Example 15,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-aminewhite solid (20.2 mg, 3%): LCMS m/z = 391 [M+H]+; 1H NMR (500 MHz,DMSO-d6) δ: 12.36 (s, 1H), 10.93 (s, 1H), 8.58 (d, 1H), 8.27 (s, 1H),7.80-7.70 (m, 1H), 7.36-7.34 (m, 1H), 7.33 (t, 1H), 7.12-7.10 (m, 1H),6.92-6.89 (m, 1H), 5.84 (s, 1H), 5.50-5.34 (m, 2H).

Peak 2, Example 16,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-aminewhite solid (13.2 mg, 2%): LCMS m/z = 391 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ: 12.36 (s, 1H), 10.92 (s, 1H), 8.59 (d, 1H), 8.27 (s, 1H),8.23 (s, 1H), 7.73 (td, 1H), 7.33 (dd, 1H), 7.30 (t, 1H), 7.11 (d, 1H),6.92-6.88 (m, 1H), 5.85-5.83 (m, 1H), 5.48-5.30 (m, 2H).

Example 17(S)-3-chloro-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of(S)-3,6-dichloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 63, 89 mg, 0.285 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (47 mg, 0.314 mmol),^(t)BuBrettPhos Pd G3 (12 mg, 14 mmol) and KOAc (84 mg, 0.855 mmol) indioxane (1 mL) was stirred at 90° C. for 1 h. The reaction mixture wasevaporated to dryness and the residue dissolved in DCM, filtered andpurified by Isco (0-10% MeOH/DCM) to afford the title compound as a paleyellow solid (46.4 mg, 38%). LCMS m/z = 425 [M+H]⁺; 1H NMR (500 MHz,DMSO-d₆) δ: 12.31 (s, 1H), 11.06 (s, 1H), 8.25 (s, 1H), 8.18 (d, 1H),8.04-7.93 (m, 1H), 7.50-7.11 (m, 2H), 6.67 (q, 1H), 5.99 (d, 1H), 1.87(d, 3H).

Example 18 and 19(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of6-chloro-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 85, 180 mg, 0.65 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (115 mg, 0.78 mmol), KOAc (190mg, 1.94 mmol) and BrettPhos Pd G4 (40 mg) in dioxane (5 mL) was stirredat 90° C. for 2 h. The mixture was evaporated to dryness in vacuo andthe residue purified by flash chromatography (SiO₂, 3:1 EtOAc/PE)followed by prep-HPLC-1 to affordN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(~100 mg). This was separated by chiral Prep-SFC (Daicel AD, 20 x 250mm, 10 mm; 35% MeOH (0.2% MeOH/NH₃) in CO₂ to give the title compounds.

Peak 1, Example 18,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(25.9 mg, 10%): LCMS m/z = 391 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ:12.34 (s, 1H), 10.94 (s, 1H), 8.72 (s, 1H), 8.53-8.50 (m, 1H), 8.30 (s,1H), 8.22 (s, 1H), 7.86 (d,1H), 7.38 (dd, 1H), 7.33 (t, 1H), 6.96-6.90(m, 1H), 5.90-5.87 (m, 1H), 5.39-5.05 (m, 2H).

Peak 2, Example 19,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(30.7 mg, 12%): LCMS m/z = 391 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ:12.50-11.90 (br, 1H), 11.30-10.85 (br, 1H), 8.72-8.70 (m, 1H), 8.53-8.51(m, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 7.86 (d, 1H), 7.39 (dd, 1H), 7.32(t, 1H), 6.96-6.90 (m, 1H), 5.91 (s, 1H), 5.41-5.05 (m, 2H).

Example 20 and 21(S)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-blpyrazin-1-yl)methyl)pyrrolidin-2-oneand(R)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one

A mixture of4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one(Preparation 64, 152 mg, 0.60 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (99 mg, 0.66 mmol), KOAc (178 mg,1.81 mmol) and BrettPhos Pd G4 (26 mg) in dioxane (2 mL) was stirred at90° C. for 2 h. The mixture was diluted with 5% MeOH/DCM and washed withwater. The combined organics were dried (Na₂SO₄) and evaporated todryness in vacuo and the residue purified by Isco chromatography (SiO₂,0-10% MeOH/DCM) afford4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one(89 mg, 40%). The racemate was separated by chiral Prep-SFC (Daicel AD,20 x 250 mm, 10 mm; 40% MeOH (0.2% MeOH/NH3) in CO2 to give the titlecompounds.

Peak 1, Example 20,(S)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-oneor(R)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one(Yellow solid, 30.5 mg, 68%); LCMS m/z = 365 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ: 12.64-11.74 (br s, 1H), 11.74-10.38 (br s, 1H), 8.18 (s,1H), 8.16 (s, 1H), 7.78 (s, 1H), 7.30 (t, 1H), 5.86 (s, 1H), 4.82-4.72(m, 1H), 4.53 (dd, 1H), 3.11-3.07 (m, 1H), 2.96-2.92 (m, 1H), 2.89-2.83(m, 1H), 2.04-1.97 (m, 1H), 1.87-1.79 (m, 1H).

Peak 2, Example 21,(R)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-oneor(S)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one(Yellow solid, 33.2 mg, 74%); LCMS m/z = 365 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ: 12.35 (s, 1H), 10.85 (s, 1H), 8.18 (s, 1H), 8.17 (s, 1H),7.78 (s, 1H), 7.30 (t, 1H,), 5.83 (s, 1H), 4.82-4.77 (m, 1H), 4.53 (dd,1H), 3.11-3.06 (m, 1H), 2.96-2.92 (m, 1H), 2.89-2.83 (m, 1H), 2.04-1.97(m, 1H), 1.86-1.81 (m, 1H).

Example 22(S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of(S)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 90, 350 mg, 1.31 mmol), 5-methoxy-1H-pyrazol-3-aminehydrochloride (294 mg, 1.97 mmol), BrettPhos Pd G4 (20 mg, 0.21 mmol)and KOAc (643 mg, 6.56 mmol) in dioxane (10 mL) was stirred at 90° C.overnight under N₂. The reaction mixture was cooled to rt and evaporatedto dryness in vacuo. The residue was purified by flash chromatography(SiO₂, 50% EtOAc/PE) followed by prep-HPLC-1 to afford the titlecompound as a white solid (116 mg, 25%). LCMS m/z = 344 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ: 12.10-11.60 (m, 1H), 10.59 (br s, 1H), 8.16 (s,1H), 8.12 (s, 1H), 5.62 (br s, 1H), 4.93 (s, 1H), 3.90-3.81 (m, 1H),3.81 (s, 3H), 3.76-3.71 (m, 1H), 3.30-3.20 (m, 1H), 3.15-3.11 (m, 1H),2.00-1.96 (m, 1H), 1.71-1.66 (m, 1H), 1.47 (d, 3H), 1.40-1.25 (m, 1H),1.25-1.11 (m, 1H), 0.93-0.85 (m, 1H).

Example 231-(2-cyclopropylpropan-2-yl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of6-chloro-1-(2-cyclopropylpropan-2-yl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 79, 100 mg, 0.422 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (62.9 mg, 0.422 mmol), BrettPhosPd G4 (64.6 mg, 0.042 mmol) and KOAc (123 mg, 1.26 mmol) in dioxane (2mL) was degassed with N₂ (x3) and heated at 90° C. for 3h under N₂. Thereaction mixture was cooled to rt and evaporated to dryness in vacuo.The residue was purified by flash column chromatography (50% EtOAc/PE)followed by prep-HPLC-1 to give the title compound as a yellow solid(25.2 mg, 17%). LCMS m/z = 349 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ:12.30-11.48 (br, 1H), 11.06-10.26 (br, 1H), 8.19 (s, 1H), 8.07 (s, 1H),7.22 (t, 1H), 6.22 (s, 1H), 1.68 (s, 6H), 1.65-1.62 (m, 1H), 0.36-0.33(m,4 H).

Example 24 and 25(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of6-chloro-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 86, 1.1 g, 4.23 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (693 mg, 4.65 mmol), BrettPhos PdG4 (195 mg, 0.21 mmol) and KOAc (1.24 g, 12.7 mmol) in dioxane (20 mL)was degassed with N₂ (x3) and then heated at 100° C. overnight under N₂.The reaction mixture was cooled to rt and evaporated to dryness invacuo. The residue was purified by flash chromatography (SiO₂, 4:1EtOAc/PE) and then by prep-HPLC-1 to giveN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(600 mg, 38%). The racemate (600 mg) was separated by chiral-SFC (DaicelAD, 20 x 250 mm, 10 mm; 40% MeOH (0.2% MeOH/NH₃) in CO₂ to afford thetitle compounds as white solids.

Peak 1, Example 24,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(297 mg): LCMS m/z = 374 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.29 (s,1H), 10.88 (s, 1H), 9.15 (t, 1H), 8.25 (s, 1H), 8.23 (s, 1H), 7.63 (dd,1H), 7.37 (d, 1H), 7.31 (t, 1H), 6.83 (q, 1H), 5.87 (s, 1H), 2.02 (d,3H).

Peak 2, Example 25,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(269 mg, 89%): LCMS m/z = 374 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.28(br s, 1H), 10.87 (br s, 1H), 9.14 (dd, 1H), 8.24 (s, 1H), 8.22 (s, 1H),7.62 (dd, 1H), 7.36 (dd, 1H,), 7.30 (t, 1H), 6.83-6.80 (m, 1H), 5.85 (s,1H), 2.00 (d, 3H).

Example 26 and 27(1R,2R)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrileand(1S,2S)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile

A mixture oftrans-rac-2-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile(Preparation 94, 370 mg, 1.58 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (235 mg, 1.58 mmol), BrettPhos PdG4 (145 mg, 0.158 mmol) and KOAc (465 mg, 4.74 mmol) in dioxane (10 mL)was stirred at 100° C. overnight under N₂. The reaction mixture wascooled to rt and concentrated to give a residue which was purified byflash chromatography (SiO₂, 50% EtOAc/PE) and by prep-HPLC-1 to give theracemic mixture of title compounds (200 mg, 36%). The racemic mixturewas separated by chiral-SFC (Daicel OD, 20 x 250 mm, 10 mm; 30% IPA(+0.2% MeOH/NH₃) in CO₂ to afford the title compounds as yellow solids.

Peak 1, Example 26,(1R,2R)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrileor(1S,2S)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile(83.6 mg): LCMS m/z = 347 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.24 (s,1H), 10.84 (s, 1H), 8.21 (s, 1H), 8.20 (s, 1H), 7.32 (t, 1H), 5.88 (s,1H), 4.51 (d, 2H), 1.98 (m, 1H), 1.85 (m, 1H), 1.30 (m, 1H), 1.19 (m,1H).

Peak 2, Example 27,(1S,2S)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrileor(1R,2R)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile(90.6 mg): LCMS m/z = 347 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.25 (s,1H), 10.84 (s, 1H), 8.21 (s, 1H), 8.20 (s, 1H), 7.32 (t, 1H), 5.88 (s,1H), 4.51 (d, 2H), 2.02-1.95 (m, 1H), 1.88-1.83 (m, 1H), 1.33-1.28 (m,1H), 1.21-1.15 (m, 1H).

Example 28 and 29(S)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of6-chloro-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 93, 230 mg, 0.76 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (113 mg, 0.76 mmol), BrettPhos PdG4 (165 mg, 0.1 mmol) and KOAc (223 mg, 2.28 mmol) in dioxane (5 mL) wasdegassed with N₂ (x3) and then heated at 90° C. overnight under N₂. Thereaction mixture was cooled to rt and concentrated to give a residuewhich was purified by flash column chromatography on silica gel followedby prep-HPLC-3 to give1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(150 mg, 48%). The racemic material was separated by chiral-SFC toafford the title compounds as yellow solids.

Peak 1, Example 28,(S)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(55.4 mg): LCMS m/z = 416 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ: 12.27 (brs, 1H), 10.95 (br s, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 7.31 (t, 1H), 6.57(dt, 1H), 5.82 (s, 1H), 5.59-5.55 (m, 1H), 3.89-3.73 (m, 2H), 3.32-3.19(m, 1H), 1.84-1.80 (m, 1H), 1.50-1.21 (m, 3H), 1.01-0.97 (m, 1H).

Peak 2, Example 29,(R)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(60.6 mg): LCMS m/z = 416 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.27 (brs, 1H), 10.95(br s, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 7.31 (t, 1H), 6.57(dt, 1H), 5.82 (s, 1H), 5.59-5.55 (m, 1H), 3.89-3.73 (m, 2H), 3.32-3.19(m, 1H), 1.84-1.80 (m, 1H), 1.50-1.21 (m, 3H), 1.01-0.97 (m, 1H).

Example 30(R)-2-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-bipyrazin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol

A mixture of(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(Preparation 190, 500 mg, 0.906 mmol) and 1 M TBAF/THF was heated toreflux for 0.5 h. The reaction mixture was diluted with EtOAc and washedwith H₂O. The combined organics were evaporated to dryness in vacuo andthe residue purified by flash chromatography (SiO₂, 5:1 EtOAc/PE),followed by prep-HPLC-1 to give the title compound as a white solid (250mg, 70%). LCMS m/z = 396 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.16 (s,1H), 10.75 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.30 (t, 1H), 5.97 (s,1H), 4.81-4.79 (m, 1H), 4.68-4.65 (m, 1H), 3.94-3.85 (m, 2H), 3.84-3.81(m, 1H), 3.72-3.67(m, 1H), 3.33-3.25 (m, 1H), 3.17-3.11 (m, 1H),2.21-2.18 (m, 1H), 1.77-1.74 (m, 1H), 1.45-1.35 (m, 2H), 0.86-0.83 (m,1H).

Example 31(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

To a mixture of(R)-2-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol(Example 30, 140 mg, 0.354 mmol) in DCM (2 mL) was added DAST (114 mg,0.708 mmol) at 0° C. and the resulting mixture stirred for 2 h. Thereaction mixture was diluted with EtOAc and washed with aq NaHCO₃ andconcentrated in vacuo. The residue was purified by prep-HPLC-1 to givethe title compound as a white solid (10 mg, 7%). LCMS m/z = 398 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ: 12.21 (br, s, 1H), 10.84 (br s, 1H), 8.23(s, 1H), 8.21 (s, 1H), 7.31 (t, 1H), 5.90 (s, 1H), 5.40-5.30 (m, 1H),5.00-4.97 (m, 1H), 4.89-4.85 (m, 1H), 3.88-3.84 (m, 1H), 3.72-3.69(m,1H), 3.33-3.28 (m, 1H), 3.20-3.12 (m, 1H), 2.21-2.18 (m, 1H), 1.77-1.74(m, 1H), 1.45-1.40 (m, 1H), 1.40-1.35 (m, 1H), 0.86-0.83 (m, 1H).

Example 32 and 33(S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-blpyrazin-6-amineand(R)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

A mixture of6-chloro-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 86, 2.0 g, 7.67 mmol), 5-methoxy-1H-pyrazol-3-amine (867mg, 7.67 mmol), BrettPhos Pd G4 (352 mg, 0.383 mmol) and KOAc (3.00 g,60.6 mmol) in dioxane (20 mL) was stirred at 100° C. overnight under N₂.The reaction mixture was evaporated to dryness in vacuo and the residuepurified by flash chromatography (SiO2, 50% EtOAc/PE) followed byprep-HPLC-1 to give racemicN-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(800 mg, 30%). The racemic compound (800 mg) was separated by chiral-SFC(Daicel AD, 20 x 250 mm, 10 mm; 40% MeOH (0.2% MeOH/NH3) in CO2) toafford the title compounds as yellow solids.

Peak 1, Example 32,(S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(266 mg): LCMS m/z = 338 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.76 (brs, 1H), 10.57 (br s, 1H), 9.14 (dd, 1H), 8.22 (s,1H), 8.20 (s, 1H), 7.61(dd, 1H), 7.36 (dd, 1H), 6.70-6.52 (m, 1H), 5.70-5.52 (m, 1H), 3.82 (s,3H), 2.01 (d, 3H).

Peak 2, Example 33,(R)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(346 mg): LCMS m/z = 338 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.75 (brs, 1H), 10.58 (br s, 1H), 9.14 (dd, 1H), 8.22 (s,1H), 8.20 (s, 1H), 7.61(dd, 1H), 7.36 (dd, 1H), 6.70-6.52 (m, 1H), 5.70-5.52 (m, 1H), 3.82 (s,3H), 2.01 (d, 3H).

Example 34-140

The title compounds were prepared from the appropriate amine (Amine-1,Amine-2 or Amine-3), the appropriate chloride (RCl) and the appropriatePd catalyst system using an analogous method to that described forExample 8. Purification by ISCO or HPLC as noted in the table below.

Amine-1: 5-(difluoromethoxy)-1H-pyrazol-3-amine; Amine-2:5-ethoxy-1H-pyrazol-3-amine; Amine-3: 5-methoxy-1H-pyrazol-3-amine

Example No. Name/Structure/Amine/RCl/Catalyst/Data 34(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(R)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 37); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (22.1 mg,26%); LCMS m/z = 381 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.19 (d, 1H),10.75 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.31 (t, 1H), 5.95 (d, 1H),5.02-4.91 (m, 1H), 3.94-3.84 (m, 1H), 3.75-3.65 (m, 1H), 3.11 (td, 1H),2.14-2.01 (m, 1H), 1.76 (dt, 1H), 1.48 (d, 3H), 1.35 (qd, 1H), 1.18 (qd,1H), 0.79 (d, 1H) - one peak is obscured by water signal. 35N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 6-chloro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 38); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (35.4 mg,32%); LCMS m/z = 359 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.30 (s, 1H),10.87 (s, 1H), 8.57 (s, 1H), 8.48 (d, 1H), 8.21 (d, 2H), 7.65 (d, 1H),7.51-7.14 (m, 2H), 5.82 (s, 2H). 361-benzyl-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 1-benzyl-6-chloro-1H-pyrazolo[3,4-b]pyrazine (Preparation39); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (26.7 mg, 30%); LCMS m/z= 358 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.24 (s, 1H), 10.82 (s, 1H),8.22 (s, 1H), 8.18 (s, 1H), 7.57-6.99 (m, 7H), 5.94 (d, 1H), 5.75 (s,2H). 37N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 6-chloro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 40); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (34.5 mg,39%); LCMS m/z = 376 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.24 (s, 1H),10.85 (s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 7.49-7.07 (m, 5H), 5.93 (s,1H), 5.80 (s, 2H). 38N-(5-ethoxy-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-2; RCl:6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 87); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (20.8 mg,26%); LCMS m/z = 344 [M+H]⁺ 39N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(3-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 6-chloro-1-(3-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 41); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (37.8 mg,43%); LCMS m/z = 376 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.26 (s, 1H),10.85 (s, 1H), 8.22 (s, 1H), 8.21 (s, 1H), 7.50-7.13 (m, 2H), 7.13-7.02(m, 3H), 5.90 (s, 1H), 5.78 (s, 2H). 40N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(4-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 6-chloro-1-(4-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 42); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (24.7 mg,28%); LCMS m/z = 376 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.26 (s, 1H),10.83 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 7.48-7.08 (m, 5H), 5.92 (s,1H), 5.74 (s, 2H). 41N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 43); tBuBrettPhos Pd G3 ISCO: White solid (32 mg, 38%);LCMS m/z = 377 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.31 (s, 1H), 10.88(s, 1H), 8.26 (d, 1H), 8.21 (d, 2H), 7.92-7.80 (m, 1H), 7.51-7.08 (m,2H), 5.89 (s, 1H), 5.83 (s, 2H). 42N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 44); tBuBrettPhos Pd G3 ISCO: White solid (29 mg, 34%);LCMS m/z = 377 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.30 (s, 1H), 10.89(s, 1H), 8.51 (d, 1H), 8.42 (d, 1H), 8.22 (d, 2H), 7.58 (dt, 1H), 7.31(t, 1H), 5.94-5.82 (m, 3H). 43(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(3-fluorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(1-(3-fluorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 45); tBuBrettPhos Pd G3 ISCO: White solid (33 mg, 36%);LCMS m/z = 390 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.22 (d, 1H), 10.81(s, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 7.48-7.11 (m, 4H), 7.07 (td, 1H),6.54 (q, 1H), 5.92 (d, 1H), 1.89 (d, 3H). 441-(4,4-difluorocyclohexyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 50); tBuBrettPhos Pd G3 ISCO: Yellow solid (44 mg, 45%);LCMS m/z = 386 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.14 (s, 1H), 10.80(s, 1H), 8.20 (s, 1H), 8.18 (s, 1H), 7.31 (t, 1H), 5.93 (s, 1H),5.25-5.12 (m, 1H), 2.25-2.14 (m, 6H), 2.06-1.97 (m, 2H) 45(S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:(S)-6-chloro-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 82); tBuBrettPhos Pd G3 ISCO: Yellow solid (14 mg, 14%);LCMS m/z = 337 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 11.83 (d, 1H), 10.43(d, 1H), 8.55 (s, 1H), 8.18 (s, 2H), 7.71 (t, 1H), 7.33-7.23 (m, 1H),7.06 (d, 1H), 6.25 (d, 1H), 5.55 (s, 1H), 3.80 (s, 3H), 1.96 (d, 3H). 46(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(2-fluorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(1-(2-fluorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 46); tBuBrettPhos Pd G3 ISCO: White solid (37 mg, 32%);LCMS m/z = 390 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.17 (s, 1H), 10.78(s, 1H), 8.21 (d, 2H), 7.48-7.09 (m, 5H), 6.64 (d, 1H), 6.00 (s, 1H),1.90 (d, 3H). 47(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(1-(4-fluorophenyl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 47); tBuBrettPhos Pd G3 ISCO: White solid (49 mg, 41%);LCMS m/z = 390 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.23 (s, 1H), 10.79(s, 1H), 8.20 (d, 2H), 7.51-7.06 (m, 5H), 6.52 (q, 1H), 5.92 (d, 1H),1.88 (d, 3H). 48(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(5-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(1-(5-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 48); tBuBrettPhos Pd G3 ISCO: White solid (46 mg, 35%);LCMS m/z = 391 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.27 (s, 1H), 10.82(s, 1H), 8.52 (d, 1H), 8.21 (d, 2H), 7.64 (td, 1H), 7.47-7.12 (m, 2H),6.52 (q, 1H), 5.85 (d, 1H), 1.93 (d, 3H). 494-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydro-2H-pyran-4-ol

Amine-1; RCl:4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydro-2H-pyran-4-ol(Preparation 78); tBuBrettPhos Pd G3 ISCO: White solid (16.9 mg, 36%);LCMS m/z = 382 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.12 (s, 1H), 10.81(s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.31 (t, 1H), 5.93 (s, 1H), 4.79(s, 1H), 4.42 (s, 2H), 3.60 (d, 4H), 1.63 (dt, 2H), 1.41 (d, 2H). 50(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(3-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(1-(3-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 49); tBuBrettPhos Pd G3 ISCO: Yellow solid (55 mg, 44%);LCMS m/z = 391 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.26 (s, 1H), 10.87(s, 1H), 8.47 (d, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.67 (t, 1H),7.49-7.15 (m, 2H), 6.63 (q, 1H), 5.88 (s, 1H), 1.95 (d, 3H). 51(S)-1-(1-cyclopropylethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(1-cyclopropylethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 33); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (38.1 mg,37%); LCMS m/z = 336 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 11.89 (s, 1H),10.47 (s, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.05 (t, 1H), 5.69 (s, 1H),4.26 (t, 1H), 1.34 (d, 3H), 1.12 (q, 1H), 0.34 (dd, 1H), 0.25-0.14 (m,1H), 0.05 (q, 2H). 52N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(thiazol-4-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)thiazole (Preparation34); tBuBrettPhos Pd G3 ISCO: pale yellow solid (59 mg, 43%); LCMS m/z =365 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.38 (s, 1H), 10.85 (s, 1H),9.05 (d, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 7.51 (s, 1H), 7.30 (t, 1H),5.87 (s, 3H). 53N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(thiazol-5-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:5-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)thiazole (Preparation35); tBuBrettPhos Pd G3 ISCO: White solid (44.4 mg, 39%); LCMS m/z = 365[M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.33 (s, 1H), 10.91 (s, 1H), 9.00(s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.33 (t, 1H), 6.07(s, 2H), 5.92 (s, 1H). 54N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(thiazol-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:2-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)thiazole (Preparation52); tBuBrettPhos Pd G3 ISCO: White solid (44.7 mg, 34%); LCMS m/z = 365[M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.34 (s, 1H), 10.92 (s, 1H), 8.25(s, 1H), 8.23 (s, 1H), 7.76 (d, 1H), 7.67 (d, 1H), 7.30 (t, 1H), 6.14(s, 2H), 5.86 (s, 1H). 55(R)-1-(1-cyclopropylethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(R)-6-chloro-1-(1-cyclopropylethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 32); tBuBrettPhos Pd G3 ISCO: White solid (49.5 mg, 47%);LCMS m/z = 336 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.14 (s, 1H), 10.72(s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.30 (t, 1H), 5.94 (s, 1H),4.64-4.37 (m, 1H), 1.59 (d, 3H), 1.36 (dq, 1H), 0.59 (hept, 1H), 0.44(dd, 1H), 0.30 (q, 2H). 563-chloro-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:3,6-dichloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 68); tBuBrettPhos Pd G3 ISCO: White solid (49.6 mg, 38%);LCMS m/z = 400 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.25 (s, 1H), 11.03(s, 1H), 8.23 (s, 1H), 7.32 (t, 1H), 6.00 (s, 1H), 4.37 (d, 2H), 3.81(d, 2H), 3.24 (t, 2H), 2.21-2.09 (m, 1H), 1.46-1.27 (m, 4H). 57(1s,4s)-4-(6-((5-(difluoromethoxy)-1Hpyrazol-3-yl)amino)-1Hpyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol

Amine-1; RCl:(1s,4s)-4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol(Preparation 51); tBuBrettPhos Pd G3 ISCO: White solid (61 mg, 44%);LCMS m/z = 366 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.14 (s, 1H), 10.71(s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.31 (t, 1H), 5.99 (s, 1H), 4.86(br s, 1H), 4.50 (br s, 1H), 3.92 (s, 1H), 2.38 (d, 2H), 1.83 (d, 2H),1.66 (d, 4H). 58(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(thiazol-5-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-5-(1-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)ethyl)thiazole(Preparation 53); tBuBrettPhos Pd G3 SCO: Pale yellow solid (46.1 mg,42%); LCMS m/z = 379 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.33 (s, 1H),10.91 (s, 1H), 8.98 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H),7.33 (t, 1H), 7.00 (q, 1H), 5.89 (d, 1H), 1.93 (d, 3H). 59(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(2-methoxypyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(1-(2-methoxypyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 54); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (46 mg,37%); LCMS m/z = 403 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.13 (d, 1H),10.76 (s, 1H), 8.22 (s, 1H), 8.21 (s, 1H), 8.07 (dd, 1H), 7.53 (dd, 1H),7.30 (t, 1H), 6.94 (dd, 1H), 6.49 (q, 1H), 6.07 (d, 1H), 3.90 (s, 3H),1.84 (d, 3H). 60(S)-1-(1-(2-chloropyridin-3-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(1-(2-chloropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 55); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (42.3 mg,36%); LCMS m/z = 407 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.17 (s, 1H),10.79 (s, 1H), 8.34 (dd, 1H), 8.25 (s, 1H), 8.23 (s, 1H), 7.88 (d, 1H),7.48-7.07 (m, 2H), 6.60 (q, 1H), 6.06 (s, 1H), 1.88 (d, 3H). 61(S)-3-chloro-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-3,6-dichloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 62); tBuBrettPhos Pd G3 ISCO: Off-white solid (42.8 mg,36%); LCMS m/z = 407 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.34 (s, 1H),11.07 (s, 1H), 8.61 (s, 1H), 8.48 (d, 1H), 8.24 (s, 1H), 7.76 (d, 1H),7.55-7.15 (m, 2H), 6.65 (q, 1H), 5.94 (s, 1H), 1.89 (d, 3H). 626-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile

Amine-1; RCl:6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile(Preparation 69); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (21.7 mg,26%); LCMS m/z = 391 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.31 (s, 1H),11.20 (s, 1H), 8.38 (s, 1H), 7.32 (t1H), 6.04 (s, 1H), 4.52 (d, 2H),3.88-3.75 (m, 2H), 3.24 (t, 2H), 2.20 (br s, 1H), 1.50-1.28 (m, 4H). 63(S)-6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile

Amine-1; RCl:(S)-6-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile(Preparation 70); tBuBrettPhos Pd G3 ISCO: Yellow solid (58.4 mg, 41 %);LCMS m/z = 416 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.36 (s, 1H), 11.24(s, 1H), 8.40 (s, 1H), 8.20 (d, 1H), 8.02 (t, 1H), 7.53-7.13 (m, 2H),6.80 (q, 1H), 6.02 (s, 1H), 1.92 (d, 3H). 64(S)-6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile

Amine-1; RCl:(S)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile(Preparation 71); tBuBrettPhos Pd G3 ISCO: Yellow solid (32.6 mg, 29%);LCMS m/z = 405 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.32 (s, 1H), 11.19(s, 1H), 8.38 (s, 1H), 7.32 (t, 1H), 6.01 (s, 1H), 5.23-5.10 (m, 1H),3.89 (d, 1H), 3.71 (d, 1H), 3.14 (t, 1H), 2.14-2.04 (m, 1H), 1.74 (d,1H), 1.51 (d, 3H), 1.41-1.30 (m, 1H), 1.25-1.13 (m, 2H), 0.87 (d, 1H).65N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(((2R,4r,6S)-2,6-dimethyltetrahydro-2Hpyran-4-yl)methyl)-1Hpyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 57); tBuBrettPhos Pd G3 ISCO: Pale yellow foam (43.6 mg,31%); LCMS m/z = 394 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.16 (s, 1H),10.76 (s, 1H), 8.20 (d, 1H), 8.16 (d, 1H), 7.30 (dd, 1H), 5.99 (s, 1H),4.34 (d,), 3.40 - 3.31 (m, 2H), 2.31-2.17 (m, 1H), 1.45 (d, 2H), 1.04(d, 6H), 0.93 (q, 2H). 661-(((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:6-chloro-1-(((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 57); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (31.5 mg,20%); LCMS m/z = 358 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 11.79 (d, 1H),10.42 (d, 1H), 8.37-7.98 (m, 2H), 5.96 (d, 1H), 4.39-4.14 (m, 2H), 3.84(d, 3H), 3.37 (d, 2H), 2.25 (s, 1H), 1.45 (d, 2H), 1.04 (dd, 6H), 0.94(d, 2H). 67(S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:(S)-6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 81); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (22.2 mg,21%); LCMS m/z = 337 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 11.84 (d, 1H),10.47 (d, 1H), 8.61 (s, 1H), 8.46 (d, 1H), 8.18 (d, 2H), 7.73 (s, 1H),7.34 (dt, 1H), 6.40 (d, 1H), 6.12-5.60 (d, 1H), 3.87 (d, 3H), 2.00-1.85(m, 3H). 68(S)-1-(1-cyclopropylethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:(S)-6-chloro-1-(1-cyclopropylethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 33); tBuBrettPhos Pd G3 ISCO: Tan solid (39.2 mg, 36%);LCMS m/z = 300 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 1.76 (d, 1H), 10.37(d, 1H), 8.38-7.97 (m, 2H), 5.92 (d, 1H), 4.29 (d, 1H), 3.83 (d, 3H),1.59 (s, 3H), 1.37 (s, 1H), 0.60 (s, 1H), 0.38 (d, 3H). 691-(cyclopropylmethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl: 6-chloro-1-(cyclopropylmethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 108); tBuBrettPhos Pd G3 ISCO: Tan solid (27.4 mg, 22%);LCMS m/z = 286 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 11.79 (d, 1H), 10.40(d, 1H), 8.35-8.01 (m, 2H), 5.94 (d, 1H), 4.39-4.16 (m, 2H), 3.84 (d,3H), 1.27 (d, 1H), 0.54-0.39 (m, 4H). 70(R)-N-(5-methoxy-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:(R)-6-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 192); tBuBrettPhos Pd G3 ISCO: Tan solid (43.8 mg, 31%);LCMS m/z = 316 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 11.80 (d, 1H), 10.44(d, 1H), 8.43-8.00 (m, 2H), 5.97 (d, 1H), 4.62-4.23 (m, 2H), 3.98-3.73(m, 4H), 3.63 (dd, 3H), 2.81 (s, 1H), 1.92 (s, 1H), 1.70 (dt, 1H). 71(S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(oxetan-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:(S)-6-chloro-1-(1-(oxetan-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 168); BrettPhos Pd G4 Prep-HPLC-1; Yellow solid (52 mg,21%); LCMS m/z = 316 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.71 (br s,1H), 10.75-10.16 (br s, 1H), 8.18 (br s, 1H), 8.11 (s, 1H), 5.69-5.42(m, 2H), 4.75-4.70 (m, 1H), 4.60-4.57 (m, 1H), 4.46-4.44 (m, 1H),4.25-4.22 (m, 1H), 3.82 (s, 3H), 3.56-3.50 (m, 1H), 1.41 (d, 3H). 72(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(oxetan-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(1-(oxetan-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 168); BrettPhos Pd G4 Prep-HPLC-1; Yellow solid (56 mg,28%); LCMS m/z = 352 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 12.82-11.69(br s, 1H), 11.70-10.22 (br s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.32 (t,1H), 5.95 (s, 1H), 5.58 (m, 1H), 4.74-4.71 (m, 1H), 4.53-4.50 (m, 1H),4.45-4.42 (m, 1H), 4.28-4.26 (m, 1H), 3.59-3.49 (m, 1H), 1.39 (d, 3H).73(R)-1-(1-cyclopropylethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:(R)-6-chloro-1-(1-cyclopropylethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 32); BrettPhos Pd G4 ISCO: Pale yellow foam (21.4 mg, 17%);LCMS m/z = 300 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 11.76 (d, 1H), 10.37(d, 1H), 8.36-8.01 (m, 2H), 5.92 (d, 1H), 4.29 (d, 1H), 3.80 (s, 3H),1.59 (s, 3H), 1.37 (s, 1H), 0.60 (s, 1H), 0.38 (d, 3H). 74(S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(thiazol-5-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:(S)-5-(1-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)ethyl)thiazole(Preparation 53); BrettPhos Pd G4 ISCO: Pale yellow solid (38.8 mg,36%); LCMS m/z = 343 [M+H]⁺; ¹H NMR (500 MHz, MeOH-d₄) δ: 8.91 (s, 1H),8.13 (d, 2H), 7.92 (s, 1H), 6.60 (d, 1H), 5.63 (s, 1H), 3.91 (s, 3H),2.09 (d, 3H). 75N-(5-methoxy-1H-pyrazol-3-yl)-1-(thiazol-5-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:5-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)thiazole (Preparation35); BrettPhos Pd G4 ISCO: Pale yellow solid (53.1 mg, 38%); LCMS m/z =329 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 11.89 (d, 1H), 10.54 (d, 1H),9.00 (d, 1H), 8.18 (s, 2H), 7.96 (s, 1H), 6.41-5.50 (m, 3H), 4.00 (d,1H), 3.82 (s, 2H). 761-((6-fluoropyridin-3-yl)methyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3 (as HCl salt); RCl:6-chloro-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 43); tBuBrettPhos Pd G3 ISCO: Pale yellow solid (20.1 mg,33%); LCMS m/z = 341 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ: 11.87 (d, 1H),10.51 (d, 1H), 8.37-8.07 (m, 3H), 7.85 (d, 1H), 7.14 (d, 1H), 6.30-5.54(m, 3H), 3.85 (d, 3H). 77(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl(S)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 90); tBuXphos Pd G4 prep-HPLC-4; White solid (158 mg, 30%).LCMS m/z = 380 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.20 (br s, 1H),10.74 (br s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.31 (t, 1H), 5.95 (s,1H), 5.00-4.94 (m, 1H), 3.91-3.86 (m, 1H), 3.73-3.66 (m, 1H), 3.28-3.25(m, 1H), 3.14-3.08 (m, 1H), 2.08-2.06 (m, 1H), 1.76-1.73 (m, 1H), 1.47(d, 3H), 1.34-1.16 (m, 2H), 0.80-0.77 (m, 1H). 78(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(R)-6-chloro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 106); tBuXphos Pd G3 Prep-HPLC-1; White solid (35.5 mg,30%); LCMS m/z = 352 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.05 (br s,1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.32 (t, 1H), 5.94 (s, 1H), 5.08-5.03(m, 1H), 3.98-3.92 (m, 2H), 3.72-3.66 (m, 1H), 3.41-3.33 (m, 1H),2.26-2.15 (m, 1H), 2.11-2.05 (m, 1H), 1.85-1.80 (m, 2H). 791-(tert-butyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 1-(tert-butyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 107); Pd2(dba)3, tBuXPhos Prep-HPLC-1; White solid (6.1 mg,3%); LCMS m/z = 324 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.10 (s, 1H),7.98 (s, 1H), 7.25 (t, 1H), 6.19 (s, 1H), 1.73 (s, 9H). 801-(cyclopropylmethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 6-chloro-1-(cyclopropylmethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 108); tBuXphos Pd G3 Prep-HPLC-4; White solid (11.5 mg,7%); LCMS m/z = 322 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.24 (br s,1H), 10.80 (br s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.32 (t, 1H), 5.96(s, 1H), 4.35 (d, 2H), 1.30-1.25 (m, 1H), 0.52-0.45 (m, 4H). 811-(((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:1-(((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 111); Pd₂(dba)₃, tBuXPhos Prep-HPLC-1; White solid (43.1mg, 30%); LCMS m/z = 364 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.30-12.20 (br, 1H), 10.85-10.70 (br, 1H), 8.20 (s, 1H), 8.15 (s, 1H),7.32 (t, 1H), 5.96 (br s, 1H), 4.43 (d, 2H), 3.65 (d, 2H), 3.52 (d, 2H),1.80-1.75 (m, 2H), 1.20-1.12 (m, 1H). 82(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(R)-6-chloro-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 113); tBuXphos Pd G3 Prep-HPLC-1; White solid (41.9 mg,16%); LCMS m/z = 373 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.80-10.40(br s, 1H), 8.55-8.52 (m, 1H), 8.21 (s, 1H), 8.20 (s, 1H), 7.74-7.69 (m,1H), 7.30 (t, 1H), 7.30-7.27 (m, 1H), 7.07 (d, 1H), 6.48-6.42 (m, 1H),5.87 (s, 1H), 1.96 (d, 3H). 83N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 80); tBuXphos Pd G3 prep-HPLC-3; Yellow solid (77.8 mg,44%); LCMS m/z = 352 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.27 (s, 1H),10.82 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.32 (t, 1H), 5.93 (s, 1H),5.20 (s, 1H), 4.03-4.00 (m, 2H), 3.62-3.56 (m, 2H), 2.17-2.13 (m, 2H),1.88-1.86 (m, 2H). 84N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-3-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-3-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 178); tBuXphos Pd G3 prep-HPLC-3; Yellow solid (35.4 mg,25%); LCMS m/z = 373 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.31 (s, 1H),10.87 (s, 1H), 8.55 (d, 1H), 8.48-8.46 (m, 1H), 8.16 (s, 1H), 7.63 (d,1H), 7.49-7.13 (m, 2H), 5.88 (s, 1H), 5.73 (s, 2H), 2.42 (s, 3H). 85N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(oxetan-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 6-chloro-1-(oxetan-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 114); tBuXphos Pd G3 Prep-HPLC-4; White solid (54.5 mg,33%); LCMS m/z = 338 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.26 (s, 1H),10.83 (s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.32 (t, 1H), 5.90 (s, 1H),4.79 (d, 2H), 4.65 (dd, 2H), 4.52 (t, 3.47 (heptet, 1H). 86(S)-1-((1,4-dioxan-2-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-1-((1,4-dioxan-2-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 118); tBuXphos Pd G3 Prep-HPLC-1; White solid (43.9 mg,38%); LCMS m/z = 368 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.90-9.15 (br,1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.31 (t, 1H), 6.01 (s, 1H), 4.63-4.41(m, 2H), 4.01-3.99 (m, 1H), 3.78-3.71 (m, 2H), 3.64-3.60 (m, 1H),3.52-3.45 (m, 2H), 3.41-3.35 (m, 1H). 87N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-IH-pyrazolo[3,4-b]pyrazine(Preparation 179); tBuXphos Pd G3 Prep-HPLC-5; White solid (77 mg, 27%);LCMS m/z = 380 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.15 (br s, 1H),10.73 (br s, 1H), 8.12 (s, 1H), 7.30 (t, 1H), 5.95 (s, 1H), 4.30 (d,2H), 3.82-3.77 (m, 2H), 3.28-3.19 (m, 2H), 2.43 (s, 3H), 2.15-2.11 (m,1H), 1.40-1.22 (m, 4H). 88(R)-1-((1,4-dioxan-2-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(R)-1-((1,4-dioxan-2-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 119); tBuXphos Pd G3 Prep-HPLC-4; White solid (43.9 mg,38%); LCMS m/z = 368 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆) δ: 11.45-10.85(br, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.31 (t, 1H), 6.01 (s, 1H),4.63-4.41 (m, 2H), 4.01-3.99 (m, 1H), 3.78-3.71 (m, 2H), 3.64-3.60 (m,1H), 3.52-3.45 (m, 2H), 3.41-3.35 (m, 1H). 89(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(R)-6-chloro-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazine or(S)-6-chloro-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 128); Pd₂(dba)₃, tBuXPhos Prep-HPLC-1; White solid (23.5mg, 11%); LCMS m/z = 390 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.32 (brs, 1H), 10.85 (br s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.49-7.42 (m, 2H),7.38-7.29 (m, 3H), 7.32 (t, 1H), 6.86-6.80 (m, 1H), 5.93 (s, 1H), 5.35(dt, 9.6 Hz, 1H), 5.13-4.96 (m, 1H). 90(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazine or(R)-6-chloro-1-(2-fluoro-1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 129); Pd₂(dba)₃, tBuXPhos Prep-HPLC-1; White solid (24.9mg, 12%); LCMS m/z = 390 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.32 (brs, 1H), 10.85 (br s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.49-7.42 (m, 2H),7.38-7.29 (m, 3H), 7.32 (t, 1H), 6.86-6.80 (m, 1H), 5.93 (s, 1H), 5.35(dt, 1H), 5.13-4.96 (m, 1H). 91(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(R)-6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 131); tBuXphos Pd G3 Prep-HPLC-1; White solid (1.4 mg,0.5%); LCMS m/z = 373 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.31 (br s,1H), 10.87 (br s, 1H), 8.59 (d, 1H), 8.47-8.43 (m, 1H), 8.22 (s, 1H),8.20 (s, 1H), 7.75-7.72 (m, 1H), 7.36-7.33 (m, 1H), 7.32 (t, 1H), 6.63(br s, 1H), 5.94 (s, 1H), 1.92 (d, 3H). 92N-(5-methoxy-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 87); tBuXphos Pd G3 Prep-HPLC-4; White solid (128.4 mg,16%); LCMS m/z = 330 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.63 (br s,1H), 10.38 (br s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 6.35-5.55 (m, 1H),4.50-4.22(m, 2H), 3.82-3.79 (m, 5H), 3.25-3.19 (m, 2H), 2.25-2.08 (m,1H), 1.41-1.31 (m, 4H). 93(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: (S)-6-chloro-1-(1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 133); tBuXphos Pd G3 prep-HPLC-3; White solid (272.5 mg,38%); LCMS m/z = 372 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.22 (s, 1H),10.80 (s, 1H), 8.20 (s, 1H), 8.19(s, 1H), 7.50-7.14 (m, 6H), 6.508-6.48(m, 1H), 5.94 (s, 1H), 1.89 (d, J = 6.8 Hz, 3H) 94(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)propyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(1-(pyridin-3-yl)propyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 135); tBuXphos Pd G3 Prep-HPLC-1; White solid (19.8 mg,11%); LCMS m/z = 387 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.35-12.20(br, 1H), 10.99-10.89 (br, 1H), 8.67 (d, 1H), 8.46 (dd, 1H), 8.24 (s,1H), 8.20 (s, 1H), 7.85-7.80 (m, 1H), 7.37-7.31 (m, 1H), 7.33 (t, 1H),6.35-6.30 (m, 1H), 5.95 (s, 1H), 2.55-2.45 (m, 1H), 2.30-2.20 (m, 1H),0.83 (t, 3H). 95N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 139); tBuXphos Pd G3 Prep-HPLC-5; White solid (98 mg, 34%);LCMS m/z = 373 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.27 (br s, 1H),10.85 (br s, 1H), 8.34 (dd, 1H), 8.21-8.20 (m, 2H), 7.33-7.31 (m, 1H),7.30 (t, 1H), 7.14-7.12 (m, 1H), 5.90 (s, 1H), 5.78 (s, 2H), 2.51 (s,3H). 96N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((4-methylpyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((4-methylpyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 140); tBuXphos Pd G3 Prep-HPLC-4; White solid (33 mg, 11%);LCMS m/z = 373 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.29 (s, 1H), 10.86(s, 1H), 8.36-8.31 (m, 2H), 8.22(s, 1H), 8.18 (s, 1H), 7.32 (t, 1H),7.23-7.20 (m, 1H), 7.13 (dd, 1H), 5.93 (s, 1H), 5.79 (s, 2H), 2.33 (s,3H). 97(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridin-2-yl)propyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(1-(pyridin-2-yl)propyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 136); tBuXPhos/Pd₂(dba)₃ Prep-HPLC-1; Yellow solid (80 mg,29%); LCMS m/z = 387 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.39 (s, 1H),10.86 (s, 1H), 8.57 (d, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.73 (td, 1H),7.31 (t, 1H), 7.30-7.27 (m, 1H), 7.18 (d, 1H), 6.20-6.17 (m, 1H), 5.87(s, 1H), 2.48-2.44 (m, 2H), 0.83 (t, 3H). 98N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((1-methylcyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((1-methylcyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 149); tBuXphos Pd G3 Prep-HPLC-1; Yellow solid (10.4 mg,4%); LCMS m/z = 336 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.50-11.95 (brs, 1H), 10.95-10.55 (br s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.30 (t, J=73.6 Hz, 1H), 6.02 (br s, 1H), 4.35 (s, 2H), 0.97 (s, 3H), 0.72-0.70(m, 2H), 0.33-0.30 (m, 2H). 991-((8-oxabicyclo[3.2.1]octan-3-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:1-((-8-oxabicyclo[3.2.1]octan-3-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 126); BrettPhos Pd G4 Prep-HPLC-5; Yellow solid (113 mg,26%); LCMS m/z = 392 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.13 (br s,1H), 10.52 (s, 1H), 8.53 (s, 1H), 8.20(s, 1H), 7.29 (t, 1H), 6.02 (s,1H), 4.27-4.25(m, 2H), 4.16-4.13 (m, 2H), 1.79-1.75 (m, 2H), 1.66-1.61(m, 2H), 1.44-1.30 (m, 5H). 100N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-isobutyl-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 6-chloro-1-isobutyl-1H-pyrazolo[3,4-b]pyrazine(Preparation 150); tBuXphos Pd G3 prep-HPLC-3; Yellow solid (131.5 mg,43%); LCMS m/z = 324 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.19 (s, 1H),10.78 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.31 (t, 1H), 6.02 (s, 1H),4.29 (d, 2H), 2.28-2.23 (m, 1H), 0.87 (d, 6H). 1011-(cyclobutylmethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 6-chloro-1-(cyclobutylmethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 151); tBuXphos Pd G3 prep-HPLC-3; Yellow solid (99.5 mg,33%); LCMS m/z = 336 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.21 (s, 1H),10.77 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.31 (t, 1H), 6.00 (s, 1H),4.48-4.50 (d, 2H), 2.88-2.82 (m, 1H), 1.98-1.92 (m, 2H), 1.83-1.80 (m,4H). 102(S)-1-(cyclopropyl(pyridin-2-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-(cyclopropyl(pyridin-2-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 142); tBuXPhos, Pd₂(dba)₃ Prep-HPLC-1; White solid (5.5 mg,8%); LCMS m/z = 399 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.35 (br s,1H), 10.84 (br s, 1H), 8.52 (d, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.80(td, 1H), 7.56 (d, 1H), 7.30 (t, 1H), 7.31-7.28 (m, 1H), 5.83 (s, 1H),5.53-5.49 (m, 1H), 2.13-2.05 (m, 1H), 0.79-0.72 (m, 1H), 0.67-0.63 (m,1H), 0.58-0.52 (m, 1H), 0.48-0.42 (m, 1H). 103(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 116); BrettPhos Pd G4 SiO₂, 80% EtOAc/PE; White solid (66.1mg, 45%); LCMS m/z = 366 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.24 (s,1H), 10.78 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.30 (t, 1H), 5.95 (s,1H), 4.55-4.36 (m, 2H), 3.84-3.77 (m, 2H), 3.30-3.25 (m, 1H), 1.77-1.73(m, 1H), 1.55-1.52 (m, 1H), 1.43 (s, 3H), 1.29-1.23 (m, 1H). 1041-(cyclopentylmethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 6-chloro-1-(cyclopentylmethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 152); tBuXphos Pd G3 prep-HPLC-3; Yellow solid (39.2 mg,27%); LCMS m/z = 350 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.18 (s, 1H),10.76 (s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.29 (t, 1H), 6.02 (s, 1H),4.37 (d, 2H), 1.61-1.48 (m, 7H), 1.34-1.29 (m, 2H). 1051-(cyclohexylmethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl: 6-chloro-1-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 153); tBuXPhos, Pd₂(dba)₃ prep-HPLC-3; White solid (37.6mg, 26%); LCMS m/z = 364 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.26 (brs, 1H), 10.86 (br s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.29 (t, 1H), 6.05(s, 1H), 4.29 (d, 2H), 1.96-1.90 (m, 1H), 1.65-1.50 (m, 5H), 1.20-0.98(m, 5H). 1061-(bicyclo[1.1.1]pentan-1-ylmethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:1-(bicyclo[1.1.1]pentan-1-ylmethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 154); BrettPhos Pd G4 Prep-HPLC-1; White solid (33.7 mg,12%); LCMS m/z = 348 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.15 (br s,1H), 10.76 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.30 (t, 1H), 6.01 (s,1H), 4.53 (s, 2H), 2.02-1.97 (m, 1H), 1.64 (s, 6H). 107(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(R)-6-chloro-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 117); tBuXphos Pd G3 prep-HPLC-3; White solid (45 mg, 16%);LCMS m/z = 366 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.24 (br s, 1H),10.77 (s, 1H), 8.19 (s, 1H), 8.15(s, 1H), 7.30 (t, 1H), 5.95 (s, 1H),4.57-4.54 (m, 1H), 4.40-4.38 (m, 1H), 3.83-3.81 (m, 2H), 1.77-1.76 (m,1H), 1.55-1.52 (m, 1H), 1.40-1.38 (m, 3H), 1.29-1.27 (m, 1H). 1081-((4,4-difluorocyclohexyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((4,4-difluorocyclohexyl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 157); tBuXPhos, Pd₂(dba)₃ Prep-HPLC-1; White solid (59 mg,35%); LCMS m/z = 400 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.19 (br s,1H), 10.81 (br s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.30 (t, 1H), 5.96(s, 1H), 4.43 (d, 2H), 2.15-2.05 (m, 1H), 2.05-1.93 (m, 2H), 1.83-1.68(m, 2H), 1.68-1.60 (m, 2H), 1.37-1.28 (m, 2H). 109(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(spiro[2.2]pentan-1-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(spiro[2.2]pentan-1-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(spiro[2.2]pentan-1-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 156); tBuXPhos, Pd₂(dba)₃ Prep-HPLC-1; White solid (116.4mg, 16%); LCMS m/z = 348 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.22 (brs, 1H), 10.74 (br s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.29 (t, 1H), 6.00(s, 1H), 4.50-4.38 (m, 2H), 1.68-1.61 (m, 1H), 1.05-0.97 (m, 1H),0.95-0.85 (m, 2H), 0.80-0.70 (m, 3H). 110N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 120); tBuXphos Pd G3 Prep-HPLC-1; White solid (37 mg, 13%);LCMS m/z = 380 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.45-11.95 (br s,1H), 10.90-10.60 (br s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.30 (t, 1H),6.06 (s, 1H), 4.39 (s, 2H), 3.71-3.67 (m, 2H), 3.55-3.49 (m, 2H),1.60-1.57 (m, 2H), 1.57-1.29 (m, 2H), 0.99 (s, 3H). 1111-(((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:1-(((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 110); BrettPhos Pd G4 Prep-HPLC-1; White solid (131 mg,32%); LCMS m/z = 364 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.22 (s, 1H),10.76 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.31 (t, 1H), 5.94-5.92 (m,1H), 4.43 (d, 2H), 3.65 (d, 2H), 3.52 (d, 2H), 1.77 (s, 2H), 1.24-1.14(m, 1H). 112N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 121); tBuXphos Pd G3 Prep-HPLC-1; White solid (38 mg, 18%);LCMS m/z = 384 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.20 (s, 1H), 10.86(s, 1H), 8.21 (s, 1H), 8.20 (s, 1H), 7.31 (t, 1H), 5.93 (s, 1H), 4.79(d, 2H), 3.77-3.72 (m, 2H), 3.52-3.47 (m, 2H), 1.91-1.79 (m, 2H),1.64-1.58 (m, 2H). 113(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(R)-6-chloro-1-((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 103); BrettPhos Pd G4 Prep-HPLC-4; Yellow solid (66.9 mg,22%); LCMS m/z = 352 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.47 (br s,1H), 12.19 (s, 1H), 10.73 (s, 1H), 8.17 (s, 1H), 8.15 (s, 1H),7.49-7.15(m, 2H), 7.31 (t, 1H), 5.95 (s, 1H), 4.57-4.29 (m, 3H),3.78-3.59 (m, 2H)), 1.84-1.72 (m, 4H). 114N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(((1S,2S)-2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineandN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(((1R,2R)-2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:rac-cis-6-chloro-1-((-2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 159); BrettPhos Pd G3 prep-HPLC-3; Yellow solid (70.3 mg,31%); LCMS m/z = 340 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.21 (s, 1H),10.81 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.29 (t, 1H), 5.97 (s, 1H),4.94-4.77 (m, 1H), 4.59-4.56 (m, 2H), 1.49-1.46 (m, 1H), 0.95-0.85 (m,2H). 1154-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydro-2H-pyran-4-carbonitrile

Amine-1; RCl:4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydro-2H-pyran-4-carbonitrile(Preparation 122); BrettPhos Pd G3 Prep-HPLC-4; Yellow solid (68 mg,24%); LCMS m/z = 391 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.25 (s, 1H),10.93 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.32 (t, 1H), 5.87 (s, 1H),4.87 (s, 2H), 3.90 (d, 2H), 3.48-3.41 (m, 2H), 1.85-1.82 (m, 4H). 116N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 155); BrettPhos Pd G4 Prep-HPLC-1; Yellow solid (6.2 mg,4%); LCMS m/z = 366 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.18 (br s,1H), 10.80 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.31 (t, 1H), 5.95 (s,1H), 4.84 (s, 2H), 1.93 (s, 6H). 117N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-3-fluoro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-3-fluoro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 180); BrettPhos Pd G4 Prep-HPLC-1; White solid (39.3 mg,31%); LCMS m/z = 384 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.50-12.10(br, 1H), 11.15-10.82 (br s, 1H), 8.19 (s, 1H), 7.30 (t, 1H), 6.01 (s,1H), 4.26 (d, 2H), 3.83-3.79 (m, 2H), 3.25-3.20 (m, 2H), 2.12-2.09 (m,1H), 1.42-1.29 (m, 4H). 1181-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:1-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 127); BrettPhos Pd G3 Prep-HPLC-4; White solid (100 mg,47%); LCMS m/z = 392 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.50-11.90(br, 1H), 11.10-10.60 (br, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.32 (t,1H), 6.03 (s, 1H), 4.25 (s, 2H), 3.64 (s, 2H), 3.65-3.61 (m, 1H),1.81-1.78 (m, 2H), 1.55-1.48 (m, 6H). 119N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 115); BrettPhos Pd G4 Prep-HPLC-1; Yellow solid (91.7 mg,41%); LCMS m/z = 352 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.40-12.10(br, 1H), 10.90-10.70 (br, 1H), 8.21, (s, 1H), 8.18, (s, 1H), 7.30 (t,1H), 5.94 (br s, 1H), 4.75-4.70 (m, 4H), 4.29-4.25 (m, 2H), 1.13 (s,3H). 120N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-3-fluoro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-3-fluoro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 182); BrettPhos Pd G4 Prep-HPLC-1; White solid (34.2 mg,40%); LCMS m/z = 377 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.36 (br s,1H), 11.11 (br s, 1H), 8.56 (d, 1H), 8.49 (dd, 1H), 8.23 (s, 1H), 7.66(d, 1H), 7.35 (dd, 1H), 7.31 (t, 1H), 5.93 (s, 1H), 5.70 (s, 2H). 121N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((4-(trifluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((4-(trifluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 123); BrettPhos Pd G3 Prep-HPLC-1; White solid (22.5 mg,27%); LCMS m/z = 434 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.35-11.85(br, 1H), 11.03-10.65 (br s, 1H), 8.23 (s, 1H), 8.22 (s, 1H), 7.29 (t,1H), 6.08-6.00 (m, 1H), 4.94 (s, 2H), 3.91-3.80 (m, 4H), 1.83-1.80 (m,4H). 122N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((4-(difluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((4-(difluoromethyl)tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 124); BrettPhos Pd G3 Prep-HPLC-5; White solid (73 mg,27%); LCMS m/z = 416 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.35-11.95(br s, 1H), 11.03-10.65 (br s, 1H), 8.23 (s, 1H), 8.22 (s, 1H), 7.30 (t,1H), 6.09 (t, 1H), 6.08-6.00 (m, 1H), 4.73 (s, 2H), 3.81-3.70 (m, 4H),1.70-1.50 (m, 2H), 1.47-1.38 (m, 2H). 123(S)-3-fluoro-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:(S)-6-chloro-3-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 181); BrettPhos Pd G4 Prep-HPLC-5; Yellow solid (50.7 mg,20%); LCMS m/z = 362 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.90-11.65(br, 1H), 10.80-10.50 (br, 1H), 8.18 (s, 1H), 5.80-5.60 (br, 1H), 4.75(br s, 1H), 3.90-3.81 (m, 1H), 3.81 (s, 3H), 3.76-3.71 (m, 1H),3.30-3.20 (m, 1H), 3.15-3.11 (m, 1H), 2.00-1.96 (m, 1H), 1.71-1.66 (m,1H), 1.42 (d, 3H), 1.40-1.25 (m, 1H), 1.25-1.11 (m, 1H), 0.93-0.85 (m,1H). 124(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-3-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:(S)-6-chloro-3-fluoro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 181); BrettPhos Pd G4 Prep-HPLC-1; White solid (107 mg,38%); LCMS m/z = 398 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.35-12.10(br, 1H), 11.05-10.75 (br, 1H), 8.14 (s, 1H), 7.24 (t, 1H), 5.91 (s,1H), 4.90-4.80 (m, 1H), 3.85-3.80 (m, 1H), 3.65-3.60 (m, 1H), 3.35-3.20(m, 1H), 3.15-3.01 (m, 1H), 1.98-1.86 (m, 1H), 1.71-1.66 (m, 1H), 1.35(d, 3H), 1.40-1.20 (m, 1H), 1.15-1.07 (m, 1H), 0.90-0.80 (m, 1H). 1251-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutan-1-ol

Amine-1; RCl:1-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutan-1-ol(Preparation 163); BrettPhos Pd G3 Prep-HPLC-4; White solid (73 mg,27%); LCMS m/z = 352 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.21 (s, 1H),10.82 (s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.30 (t, 1H), 5.89 (s, 1H),5.33 (s, 1H), 4.51 (s, 2H), 2.29-2.22 (m, 2H), 2.00-1.92 (m, 2H),1.65-1.63 (m, 1H), 1.47-1.45 (m, 1H). 1261-(((1R,3r,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 162); BrettPhos Pd G4 Prep-SFC (Daicel OJ, 20 x 250 mm, 10mm; 30% MeOH (0.2% MeOH/NH₃) in CO₂); White solid (9.4 mg); LCMS m/z =398 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.80-11.30 (br, 1H), 8.11 (s,1H), 8.05 (s, 1H), 7.26 (t, 1H), 6.05 (s, 1H), 4.31 (d, 2H), 3.05-2.98(m, 1H), 2.21-2.10 (m, 4H), 1.60-1.55 (m, 2H), 1.30-1.20 (m, 1H). 127N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 186); BrettPhos Pd G4 Prep-HPLC-1; White solid (34.9 mg,35%); LCMS m/z = 394 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.05 (br s,1H), 10.53 (br s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.25 (t, 1H), 6.29(s, 1H), 3.83-3.80 (m, 2H), 3.14-3.11 (m, 2H), 2.66-2.58 (m, 1H), 1.72(s, 6H), 1.37-1.27 (m, 2H), 1.13-1.08 (m, 2H). 1281-((1H-indazol-4-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:1-((1H-indazol-4-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 169); BrettPhos Pd G4 Prep-HPLC-4; Yellow solid (50.1 mg,24%); LCMS m/z = 398 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 13.13 (s, 1H),12.29 (s, 1H), 10.88 (s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 7.95 (s, 1H),7.49-7.44 (m, 2H), 7.32-7.28 (m, 2H), 6.99 (d, 1H), 6.05 (s, 2H), 5.94(s, 1H). 1291-(2-(1H-pyrazol-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:1-(2-(1H-pyrazol-4-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 170); BrettPhos Pd G4 Prep-HPLC-5; White solid (113 mg,26%); LCMS m/z = 362 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.47 (br s,1H), 12.19 (s, 1H), 10.73 (s, 1H), 8.17 (s, 1H), 8.15 (s, 1H),7.49-7.15(m, 2H), 7.31 (t, 1H), 7.31 (s, 2H), 5.95 (s, 1H), 4.63 (t,2H), 3.04 (t, 2H). 130N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-(pyridin-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(2-(pyridin-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 171); BrettPhos Pd G4 Prep-HPLC-1; Yellow solid (60 mg,72%); LCMS m/z = 373 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.18 (s, 1H),10.73 (s, 1H), 8.31 (d, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 7.33 (t, 1H),7.18-7.16 (m, 2H), 5.91 (s, 1H), 4.79 (t, 2H), 3.20 (t, 2H). 131N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((1-methyl-1H-imidazol-5-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 172); BrettPhos Pd G4 Prep-HPLC-1; White solid (6 mg, 2%);LCMS m/z = 362 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.35 (br s, 1H),10.92 (br s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.70-7.50 (m, 1H), 7.34(t, 1H), 7.10-6.85 (m, 1H), 5.94 (s, 1H), 5.78 (s, 2H), 3.58 (s, 3H).1322-(1-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropyl)acetonitrile

Amine-1; RCl:2-(1-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropyl)acetonitrile(Preparation 174); BrettPhos Pd G4 Prep-HPLC-1; White solid (52.6 mg,51%); LCMS m/z = 361 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.80-10.25(br, 1H), 8.20 (s, 1H), 8.19 (s, 1H), 7.30 (t, 1H), 6.01 (s, 1H), 4.51(s, 2H), 2.58 (s, 2H), 0.90 (t, 2H), 0.60 (t, 2H). 133N-(5-methoxy-1H-pyrazol-3-yl)-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:6-chloro-1-((3-methyloxetan-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 115); BrettPhos Pd G4 Prep-HPLC-1; White solid (213.7 mg,34%); LCMS m/z = 316 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.90-11.20(br, 1H), 10.45-9.90 (br, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 5.80 (br s,1H), 4.71 (d, 2H), 4.69 (s, 2H), 4.27 (d, 2H), 3.81 (s, 3H), 1.17 (s,3H). 134N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(isoxazol-5-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:5-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)isoxazole(Preparation 173); BrettPhos Pd G4 prep-HPLC-3; Yellow solid (18.7 mg,10%); LCMS m/z = 349 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.52 (s, 1H),8.22 (s, 2H), 7.31 (t, 1H), 6.39 (s, 1H), 6.02 (s, 2H), 5.93 (s, 1H).135N-(5-methoxy-1H-pyrazol-3-yl)-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl: 6-chloro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 38); BrettPhos Pd G4 Prep-HPLC-1; Yellow solid (36.1 mg,18%); LCMS m/z = 323 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.80 (br s,1H), 8.58 (s, 1H), 8.48 (d, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.65 (d,1H), 7.34 (dd, 1H), 5.78-5.74 (m, 3H), 3.82 (s, 3H). 1361-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:1-((2-oxabicyclo[2.2.2]octan-4-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 127); BrettPhos Pd G4 Prep-HPLC-1; Yellow solid (89.6 mg,29%); LCMS m/z = 356 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (s, 1H),8.09 (s, 1H), 5.90 (br s, 2H), 4.17 (s, 2H), 3.82 (s, 3H), 3.64 (s, 2H),3.63-3.61 (m, 1H), 1.80-1.77 (m, 2H), 1.55-1.48 (m, 7H). 1371-((2-fluoropyridin-3-yl)methyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3.HCl; RCl:6-chloro-1-((2-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 36); BrettPhos Pd G4 Prep-HPLC-1; Yellow solid (56 mg,29%); LCMS m/z = 341 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.74 (br s,1H), 10.70 (br s, 1H), 8.20- 8.17 (m, 3H), 7.76 (br s, 1H), 7.33-7.30(m, 1H), 5.77-5.60 (m, 3H), 3.81 (s, 3H). 1381-((3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:1-((3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 109); BrettPhos Pd G4 Prep-HPLC-1; Yellow solid (55 mg,30%); LCMS m/z = 328 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.05-11.55(br, 1H), 10.75-10.40 (br, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 5.73-5.51(m, 1H), 4.50-4.20 (m, 2H), 3.82 (s, 3H), 3.66-3.50 (m, 4H), 1.78-1.74(m, 2H), 1.23-1.13 (m, 1H,). 139(S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:(S)-6-chloro-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 97); BrettPhos Pd G4 Prep-HPLC-1; White solid (163 mg,28%); LCMS m/z = 330 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.85-11.55(br, 1H), 10.40-10.13 (br, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 5.80-5.65(m, 1H), 4.50-4.23 (m, 2H), 3.82 (t, 3H), 3.69-3.61 (m, 2H), 3.40-3.30(m, 1H), 3.27-3.22 (m, 1H), 2.22-2.15 (m, 1H), 1.66-1.58 (m, 2H),1.50-1.41 (m, 1H), 1.40-1.21 (m, 1H). 140(R)-N-(5-methoxy-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:(R)-6-chloro-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 98); BrettPhos Pd G4 Prep-HPLC-1; White solid (87 mg, 25%);LCMS m/z = 330 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.85-11.55 (br,1H), 10.40-10.13 (br, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 5.80-5.65 (m,1H), 4.50-4.23 (m, 2H), 3.82 (t, 3H), 3.69-3.61 (m, 2H), 3.40-3.30 (m,1H), 3.27-3.22 (m, 1H), 2.22-2.15 (m, 1H), 1.66-1.58 (m, 2H), 1.50-1.41(m, 1H), 1.40-1.21 (m, 1H).

Example 141-197

The title compounds were prepared using an analogous method to thatdescribed for Example 32 and 33, using the appropriate amine (RNH₂) andchloride (RCl) and an appropriate catalyst system as noted in the tablebelow.

Example No. Name/Structure/Reactants/Cat/HPLC/SFC/Data 141 and 142(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 96); tBuXPhos Pd G3 prep-HPLC-1; SFC: Daicel OZ, 20 x 250mm, 10 mm; 30% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 141,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 366 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.22(s, 1H), 10.85 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.32 (t, 1H), 5.98(s, 1H), 4.45-4.36 (m, 2H), 3.69-3.61 (m, 2H), 3.40-3.33 (m, 1H),3.26-3.22 (m, 1H), 2.18-2.11 (m, 1H), 1.62-1.53 (m, 2H), 1.48-1.42 (m,1H), 1.40-1.25 (m, 1H). Peak 2, Example 142,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 366 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.22(s, 1H), 10.85 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.32 (t, 1H), 5.98(s, 1H), 4.45-4.36 (m, 2H), 3.69-3.61 (m, 2H), 3.40-3.33 (m, 1H),3.26-3.22 (m, 1H), 2.18-2.11 (m, 1H), 1.62-1.53 (m, 2H), 1.48-1.42 (m,1H), 1.40-1.25 (m, 1H). 143 and 144(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 99); tBuXPhos Pd G3 prep-HPLC-1; SFC: Daicel IC, 20 x 250mm, 10 mm; 45% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 143,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-aminewhite solid; LCMS m/z = 352 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.21(s, 1H), 10.81 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.31 (t, 1H), 5.96(s, 1H), 4.52-4.44 (m, 2H), 3.79-3.74 (m, 1H), 3.69-3.32 (m, 2H),3.58-3.52 (m, 1H), 2.83-2.79 (m, 1H), 1.95-1.88 (m, 1H), 1.72-1.67 (m,1H). Peak 2, Example 144,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-aminewhite solid; LCMS m/z = 352 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.21(s, 1H), 10.81 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.31 (t, 1H), 5.96(s, 1H), 4.52-4.44 (m, 2H), 3.79-3.74 (m, 1H), 3.69-3.32 (m, 2H),3.58-3.52 (m, 1H), 2.83-2.79 (m, 1H), 1.95-1.88 (m, 1H), 1.72-1.67 (m,1H). 145 and 146(1r,3r)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutan-1-oland (1s,3s)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutan-1-ol

Amine-1; RCl: 3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutan-1-ol(Preparation 138); tBuXPhos Pd G3 Prep-HPLC-5; SFC: Daicel Chiralpak OD,20 x 250 mm, 10 mm; 30% MeOH (0.2% DEA) in CO₂ Peak 1, Example 145,(1r,3r)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutan-1-olor(1s,3s)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutan-1-ol,white solid; LCMS m/z = 338 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.24(br s, 1H), 10.80 (br s, 1H), 8.19 (s, 1H), 8.18 (s, 1H), 7.32 (t, 1H,5.94 (br s, 1H), 5.38 (d, 1H), 5.13 (br s, 1H), 4.10-4.00 (m, 1H),2.80-2.70 (m, 2H), 2.60-2.50 (m, 2H). Peak 2, Example 146,(1s,3s)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutan-1-olor(1r,3r)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutan-1-ol,yellow solid; LCMS m/z = 338 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.36(br s, 1H), 10.85 (br s, 1H), 8.19 (s, 1H), 8.18 (s, 1H), 7.31 (t, 1H),5.96 (s, 1H), 5.69 (s, 1H), 5.26 (d, 1H), 4.58 (s, 1H), 2.75-2.68 (m,2H), 2.46-2.40 (m, 2H). 147 and 148(R)-1-(cyclopropyl(pyridin-3-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(S)-1-(cyclopropyl(pyridin-3-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(cyclopropyl(pyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 141); tBuXPhos Pd G3 prep-HPLC-1; SFC: Daicel IC, 20 x 250mm, 10 mm; 45% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 147,(R)-1-(cyclopropyl(pyridin-3-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-1-(cyclopropyl(pyridin-3-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 399 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.25-12.10 (br, 1H), 10.99-10.89 (br, 1H), 8.68 (d, 1H), 8.49-8.46 (m,1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.86-7.80 (m, 1H), 7.39-7.36 (m, 1H),7.32 (t, 1H), 5.84 (s, 1H), 5.75-5.70 (m, 1H), 2.00-1.94 (m, 1H),0.79-0.72 (m, 1H), 0.67-0.63 (m, 1H), 0.58-0.52 (m, 1H), 0.48-0.42 (m,1H). Peak 2, Example 148,(S)-1-(cyclopropyl(pyridin-3-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-1-(cyclopropyl(pyridin-3-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,yellow solid; LCMS m/z = 399 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.25-12.10 (br, 1H), 10.99-10.89 (br, 1H), 8.68 (d, 1H), 8.49-8.46 (m,1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.86-7.80 (m, 1H), 7.39-7.36 (m, 1H),7.32 (t, 1H), 5.84 (s, 1H), 5.75-5.70 (m, 1H), 2.00-1.94 (m, 1H),0.79-0.72 (m, 1H), 0.67-0.63 (m, 1H), 0.58-0.52 (m, 1H), 0.48-0.42 (m,1H). 149 and 150(R)-1-(2,2-difluoro-1-(pyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(S)-1-(2,2-difluoro-1-(pyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(2,2-difluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 56); tBuXPhos Pd G3 Reverse phase Isco (0 to 80%MeCN/water + 0.1% TFA). Neutralized with NaHCO_(3;) SFC: Daicel IG, 20 x250 mm, 10 mm; 20% IPA (0.1% MeOH/NH₃) in CO₂ Peak 1, Example 149,(R)-1-(2,2-difluoro-1-(pyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-1-(2,2-difluoro-1-(pyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 409 [M+H]⁺; ¹H NMR (400 MHz, MeOH-d₄) δ: 8.73(d, 1H), 8.17 (s, 1H), 8.16 (s, 1H), 7.88 (td, 1H), 7.68 (d, 1H), 7.44(dd, 1H), 7.19 (m, 1H), 7.05 (t, 1H), 6.46-6.44 (m, 1H), 5.76 (s, 1H).Peak 2, Example 150,(S)-1-(2,2-difluoro-1-(pyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-1-(2,2-difluoro-1-(pyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 409 [M+H]⁺; ¹H NMR (400 MHz, MeOH-d₄) δ: 8.61(d, 1H), 8.05 (s, 1 Hz), 8.04 (s, 1H), 7.74 (td, 1H), 7.56 (d, 1H), 7.32(dd, 1H), 7.07 (dt, 1H), 6.93 (t, 1H), 6.38-6.32 (m, 1H), 5.64 (s, 1H).151 and 152(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 143); Pd₂(dba)₃/^(t)BuXPhos Prep-HPLC-5; SFC: Daicel AS, 20x 250 mm, 10 mm; 20% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 151,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 391 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.45-12.10 (br, 1H), 10.95-10.61 (br, 1H), 8.28 (d, 1H), 8.23 (s, 1H),8.21 (s, 1H), 7.98-7.93 (m, 1H), 7.33 (t, 1H), 7.16-7.11 (m, 1H),6.70-6.60 (m, 1H), 5.91 (br s, 1H), 1.90 (d, 3H). Peak 2, Example 152,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,yellow solid; LCMS m/z = 391 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.30(br s, 1H), 10.85 (br s, 1H), 8.28 (d, 1H), 8.23 (s, 1H), 8.21 (s, 1H),7.98-7.93 (m, 1H), 7.33 (t, 1H), 7.16-7.11 (m, 1H), 6.70-6.60 (m, 1H),5.91 (br s, 1H), 1.90 (d, 3H). 153 and 154(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(5-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(5-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(1-(5-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 144); tBuXPhos Pd G3 prep-HPLC-1; SFC: Daicel OZ 20 x 250mm, 10 mm; 25% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 153,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(5-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(5-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 391 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.45-12.10 (br, 1H), 10.95-10.61 (br, 1H), 8.50-8.45 (m, 2H), 8.25 (s,1H), 8.22 (s, 1H), 7.69 (dt, 1H), 7.33 (t, 1H), 6.73-6.64 (m, 1H), 5.90(br s, 1H), 1.92 (d, 3H) Peak 2, Example 154,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(5-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(5-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,yellow solid; LCMS m/z = 391 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.45-12.10 (br, 1H), 11.05-10.61 (br, 1H), 8.50-8.45 (m, 2H), 8.24 (s,1H), 8.21 (s, 1H), 7.68 (dt, 1H), 7.32 (t, 1H), 6.71-6.64 (m, 1H), 5.93(s, 1H), 1.92 (d, 3H). 155 and 156(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(1-(6-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 145); Pd₂(dba)₃/^(t)BuXPhos prep-HPLC-1; SFC: Daicel AD 20x 250 mm, 10 mm; 30% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 155,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 391 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.24(s, 1H), 10.83 (s, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 7.92-7.87 (m, 1H),7.28 (t, 1H), 7.06 (dd, 1H), 6.94 (dd, 1H), 6.56-6.52 (m, 1H), 5.85 (s,1H), 1.91 (d, 3H). Peak 2, Example 156,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(6-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,yellow solid; LCMS m/z = 391 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.50-12.10 (br, 1H), 11.05-10.75 (br, 1H), 8.23 (s, 1H), 8.22 (s, 1H),7.92-7.87 (m, 1H), 7.28 (t, 1H), 7.06 (dd, 1H), 6.94 (dd, 1H), 6.56-6.52(m, 1H), 5.87 (s, 1H), 1.91 (d, 3H). 157 and 158(S)-1-(cyclopropyl(tetrahydro-2H-pyran-4-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-1-(cyclopropyl(tetrahydro-2H-pyran-4-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(cyclopropyl(tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 125); BrettPhos Pd G4 prep-HPLC-1; SFC: Daicel OJ 20 x 250mm, 10 mm; 40% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 157,(S)-1-(cyclopropyl(tetrahydro-2H-pyran-4-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-1-(cyclopropyl(tetrahydro-2H-pyran-4-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 405 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.25-12.01 (br, 1H), 10.95-10.75 (br, 1H), 8.19 (s, 1H), 8.16 (s, 1H),7.30 (t, 1H), 5.91 (s, 1H), 4.12-4.05 (m, 1H), 3.93-3.90 (m, 1H),3.73-3.70 (m, 1H), 3.35-3.29 (m, 1H), 3.18-3.14 (m, 1H), 2.00-1.95 (m,1H), 1.44-1.39 (m, 2H), 1.35-1.20 (m, 2H), 0.87-0.83 (m, 1H), 0.71-0.69(m, 1H), 0.56-0.55 (m, 1H), 0.27-0.23 (m, 1H), 0.06-0.05 (m, 1H). Peak2, Example 158,(R)-1-(cyclopropyl(tetrahydro-2H-pyran-4-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-1-(cyclopropyl(tetrahydro-2H-pyran-4-yl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 405 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.12(br s, 1H), 10.88 (br s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.30 (t, 1H),5.91 (s, 1H), 4.13 (s, 1H), 3.93-3.90 (m, 1H), 3.73-3.70 (m, 1H), 3.15(t, 1H), 2.42-2.39 (m, 1H), 2.00 (d, 1H), 1.45-1.23 (m, 4H), 0.87-0.83(m, 1H), 0.71-0.69 (m, 1H), 0.56-0.55 (m, 1H), 0.27-0.23 (m, 1H),0.06-0.05 (m, 1H). 159 and 160N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(((1R,2S)-2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineandN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(((1S,2R)-2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:trans-rac-6-chloro-1-(((1R,2S)-2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 160); Pd₂(dba)₃/^(t)BuXPhos prep-HPLC-1; SFC: Daicel OJ 20x 250 mm, 10 mm; 15% IPA (0.5% MeOH/NH₃) in CO₂ Peak 1, Example 159,N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(((1R,2S)-2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(((1S,2R)-2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 340 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.24(s, 1H), 10.86 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.32 (t, 1H), 5.91(s, 1H), 4.90-4.71 (m, 1H), 4.40 (d, 2H), 1.85-1.70 (m, 1H), 1.15-1.02(m, 1H), 0.82-0.78 (m, 1H). Peak 2, Example 160,N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(((1S,2R)-2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(((1R,2S)-2-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 340 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.24(s, 1H), 10.86 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.32 (t, 1H), 5.91(s, 1H), 4.90-4.71 (m, 1H), 4.40 (d, 2H), 1.85-1.70 (m, 1H), 1.15-1.02(m, 1H), 0.82-0.78 (m, 1H). 161 and 162(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(oxetan-3-yl(phenyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(oxetan-3-yl(phenyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(oxetan-3-yl(phenyl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 134); BrettPhos Pd G4 prep-HPLC-1; SFC: Daicel OJ 20 x 250mm, 10 mm; 50% MeOH (0.2% MeOH/NH₃) Peak 1, Example 161,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(oxetan-3-yl(phenyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(oxetan-3-yl(phenyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 414 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.49-11.18 (br, 1H), 8.16 (s, 1H), 8.15 (s, 1H), 7.40 (s, 1H), 7.39 (s,1H), 7.34 (t. 1H), 7.31-7.24 (m, 3H), 6.74 (d, 1H), 5.92 (s, 1H),4.66-4.59 (m, 2H), 4.52 (t, 1H), 4.33 (t, 1H), 4.30-4.20 (m, 1H). Peak2, Example 162,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(oxetan-3-yl(phenyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(oxetan-3-yl(phenyl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 414 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.15(s, 1H), 8.15 (s, 1H), 7.52-7.15 (m, 6H), 6.73 (d, 1H), 5.92 (s, 1H),4.66-4.62 (m, 2H), 4.62-4.60 (m, 1H), 4.54-4.50 (m, 1H), 4.36-4.22 (m,1H). 163 and 164(S)-1-((2,2-difluorocyclopropyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-1-((2,2-difluorocyclopropyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 161); tBuXPhos Pd G3 prep-HPLC-1; SFC: Daicel OJ 20 x 250mm, 10 mm; 15% IPA (0.5% MeOH/NH₃) in CO₂ Peak 1, Example 163,(S)-1-((2,2-difluorocyclopropyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-1-((2,2-difluorocyclopropyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 358 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.23(s, 1H), 8.20 (s, 1H), 7.31 (t, 1H), 5.98 (s, 1H), 4.64-4.62 (m, 2H),2.29-2.25 (m, 1H), 1.70-1.67 (m, 1H), 1.54-1.49 (m, 1H). Peak 2, Example164,(R)-1-((2,2-difluorocyclopropyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-1-((2,2-difluorocyclopropyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 358 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.22(s, 1H), 8.19 (s, 1H), 7.30 (t, 1H), 5.96 (s, 1H), 4.63-4.60 (m, 2H),2.27-2.26 (m, 1H), 1.69-1.65 (m, 1H), 1.53-1.48 (m, 1H). 165 and 166(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-methyltetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-methyltetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((3-methyltetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 100); tBuXPhos Pd G3 prep-HPLC-1; SFC: Daicel OX 20 x 250mm, 10 mm; 30% EtOH (0.5% MeOH/NH₃) in CO₂ Peak 1, Example 165,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-methyltetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-methyltetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 366 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.56(br, 2H), 8.20 (s, 1H), 8.17 (s, 1H), 7.30 (t, 1H), 6.02 (s, 1H), 4.45(dd, 1H), 3.86-3.76 (m, 3H), 3.29 (d, 1H), 2.05-2.01 (m, 1H), 1.66-1.60(m, 1H), 1.00 (s, 3H). Peak 2, Example 166,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-methyltetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-methyltetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 366 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.19(br s, 1H), 10.82 (br s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.30 (t, 1H),5.90 (br s, 1H), 4.53-4.40 (m, 2H), 3.85-3.75 (m, 3H), 3.31-3.27 (m,1H), 2.04-2.02 (m, 1H), 1.67-1.63 (m, 1H), 1.00 (s, 3H). 167 and 168(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-fluorotetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-fluorotetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-((3-fluorotetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 101); tBuXPhos Pd G3 Prep-HPLC-2; SFC: (Daicel AD 20 x 250mm, 10 mm; 20% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 167,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-fluorotetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-fluorotetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 370 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.22(s, 1H), 10.87 (s, 1H), 8.22-8.20 (m, 2H), 7.30 (t, 1H), 5.90 (s, 1H,),5.11-4.90 (m, 2H), 4.05-3.75 (m, 4H), 2.41-2.25 (m, 1H), 2.16-2.01 (m,1H). Peak 2, Example 168,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-fluorotetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((3-fluorotetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 370 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18(d, 2H), 7.30 (t, 1H), 5.93 (s, 1H), 5.07 (t, 1H), 4.88 (dd, 1H),4.04-3.75 (m, 4H), 3.37 (br s, 2H), 2.50-2.00 (m, 2H). 169 and 170(S)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydrofuran-3-carbonitrileand(R)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydrofuran-3-carbonitrile

Amine-1; RCl:3-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydrofuran-3-carbonitrile(Preparation 102) prep-HPLC-2; SFC: Daicel AD 20 x 250 mm, 10 mm; 20%MeOH (0.5% MeOH/NH₃) in CO₂ Peak 1, Example 169,(S)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydrofuran-3-carbonitrileor(R)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydrofuran-3-carbonitrile,white solid; LCMS m/z = 377 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.27(br s, 1H), 10.95 (br s, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 7.31 (t, 1H),5.89 (s, 1H,), 5.06 (d, 1H), 4.80 (d, 1H), 4.03 (s, 2H), 3.91 (t, 2H),2.39 (t, 2H). Peak 2, Example 170,(R)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydrofuran-3-carbonitrileor(S)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydrofuran-3-carbonitrile,white solid; LCMS m/z = 377 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.22(br s, 1H), 11.03 (br s, 1H), 8.26 (s, 1H), 8.23 (s, 1H), 7.31 (t, 1H),5.91 (br s, 1H), 5.06 (d, 1H), 4.80 (d, 1H), 4.03 (s, 2H), 3.90 (dd,2H), 2.39 (t, 2H). 171 and 172(1s,4s)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclohexan-1-oland(1r,4r)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclohexan-1-ol

Amine-1; RCl:4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclohexan-1-ol(Preparation 158); tBuXPhos Pd G3 prep-HPLC-5; SFC Daicel IG 20 x 250mm, 10 mm; 30% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 171,(1s,4s)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclohexan-1-olor(1r,4r)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclohexan-1-ol,white solid; LCMS m/z = 380 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.26(br s, 1H), 10.78 (br s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.31 (t, 1H),5.95 (s, 1H), 4.90-4.85 (m, 1H), 4.50 (t, 1H), 3.38-3.30 (m, 2H),1.96-1.88 (m, 6H), 1.50-1.46 (m, 1H), 1.26-1.15 (m, 2H). Peak 2, Example172,(1r,4r)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclohexan-1-olor(1s,4s)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclohexan-1-ol,white solid; LCMS m/z = 380 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.35-12.10 (br, 1H), 10.85-10.65 (br, 1H), 8.20 (s, 1H), 8.14 (s, 1H),7.31 (t, 1H), 6.02 (br s, 1H), 4.43 (d, 2H), 4.29 (d, 2H), 3.75-3.70 (m,1H), 1.99-1.95 (m, 1H), 1.61-1.56 (m, 2H), 1.45-1.26 (m, 4H), 1.25-1.22(m, 2H). 173 and 174(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

mine-1; RCl:6-chloro-1-(1-(4-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 146); BrettPhos Pd G4 SiO₂, 75% EtOAc/PE; SFC: Daicel OX 20x 250 mm, 10 mm; 35% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 173,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 391 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.50-11.90 (br s, 1H), 11.30-10.85 (br s, 1H), 8.53 (d, 1H), 8.37 (d,1H), 8.24 (s, 1H), 8.20 (s, 1H), 7.35-7.27 (m, 1H), 7.29 (t, 1H),6.73-6.70 (m, 1H), 5.95 (s, 1H), 1.90 (d, 3H). Peak 2, Example 174,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine,white solid; LCMS m/z = 391 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.25(br s, 1H), 10.94 (br s, 1H), 8.53 (d, 1H), 8.37 (d, 1H), 8.28 (d, 2H),7.30-7.20 (m, 2H), 6.73 (br s, 1H), 5.94 (br s, 1H), 1.90 (d, 3H). 175and 176(R)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-oland(S)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol

Amine-1; RCl:1-(6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol(Preparation 75); BrettPhos Pd G4 Reverse phase Isco (0 to 70%MeCN/water + 0.1% TFA). Neutralized with NaHCO₃.; SFC: Daicel OJ 20 x250 mm, 10 mm; 30% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 175,(R)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-olor(S)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol,white solid; LCMS m/z = 410 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.15(s, 1H), 10.76 (s, 1H), 8.16 (s, 1H), 7.30 (t, 1H), 5.97 (s, 1H), 5.20(d, 1H), 5.04 (q, 1H), 4.31 (d, 2H), 3.83-3.80 (m, 2H), 3.24-3.20 (m,2H), 2.16-2.11 (m, 1H), 1.58 (d, 3H), 1.42-1.27 (m, 6H). Peak 2, Example176,(S)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-olor(R)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol,white solid; LCMS m/z = 410 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.15(s, 1H), 10.75 (s, 1H), 8.16 (s, 1H), 7.30 (t, 1H), 5.97 (s, 1H), 5.20(d, 1H), 5.04 (q, 1H), 4.31 (d, 2H), 3.83-3.80 (m, 2H), 3.24-3.20 (m,2H), 2.16-2.11 (m, 1H), 1.58 (d, 3H), 1.42-1.27 (m, 6H). 177 and 178(R)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-oland(S)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol

Amine-1; RCl:1-(6-chloro-1-((S)-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol(Preparation 77); BrettPhos Pd G4 Reverse Phase-ISCO: (0 to 80%MeCN/water + 0.1% TFA). Neutralized with NaHCO_(3;) SFC: Daicel OD 20 x250 mm, 10 mm; 30% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 177,(R)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-olor(S)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol,white solid; LCMS m/z = 417 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.25(br s, 1H), 10.81 (br s, 1H), 8.57 (d, 1H), 8.44 (dd, 1H), 8.16 (s, 1H),7.73 (dt, 1H), 7.33 (dd, 1H), 7.31 (t, 1H), 6.55-6.50 (m, 1H), 5.92 (s,1H), 5.25-5.22 (m, 1H), 5.07-5.03 (m, 1H), 1.89 (d, 3H), 1.58 (d, 3H).Peak 2, Example 178,(S)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-olor(R)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol,white solid; LCMS m/z = 417 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.50-10.50 (br, 2H), 8.57 (d, 1H), 8.44 (dd, 1H), 8.16 (s, 1H), 7.73(dt, 1H), 7.33 (dd, 1H), 7.31 (t, 1H), 6.55-6.50 (m, 1H), 5.92 (s, 1H),5.25-5.22 (m, 1H), 5.07-5.03 (m, 1H), 1.89 (d, 3H), 1.58 (d, 3H). 179and 180(1R,2S)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropan-1-oland(1S,2R)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropan-1-ol

Amine-1; RCl:2-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropan-1-ol(Preparation 185); BrettPhos Pd G4 prep-HPLC-1 ; SFC: Daicel OD 20 x 250mm, 10 mm; % MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 179,(1R,2S)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropan-1-olor(1S,2R)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropan-1-ol;LCMS m/z = 338 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.28 (br s, 1H,10.90 (br s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.28 (t, 1H), 5.94 (br s,1H), 5.62 (br s, 1H), 4.49 (ddd, 2H), 1.23-1.17 (m, 1H), 0.65-0.62 (m,1H), 0.42-0.40 (m, 1H). Peak 2, Example 180,(1S,2R)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropan-1-olor(1R,2S)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropan-1-ol;LCMS m/z = 338 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.40-12.12 (br,1H), 11.05-10.80 (br, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.28 (t, 1H),6.00-5.92 (m, 1H), 5.62 (br s, 1H), 4.52-4.46 (m, 2H), 3.42-3.33 (m,2H), 1.21-1.15 (m, 1H), 0.65-0.62 (m, 1H), 0.41-0.40 (m, 1H). 181 and182(R)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-oland(S)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol

Amine-1; RCl:1-(6-chloro-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol(Preparation 76); tBuXPhos Pd G3 Isco: SiO₂ (0 to 8% MeOH/DCM); SFC:Daicel OZ 20 x 250 mm, 10 mm; 30% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1,Example 181,(R)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-olor(S)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol;LCMS m/z = 424 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.16 (s, 1H), 10.75(s, 1H), 8.17 (s, 1H), 7.30 (t, 1H), 5.94 (s, 1H), 5.19 (d, 1H),5.05-5.02 (m, 1H), 4.92-4.85 (m, 1H), 3.90-3.85 (m, 1H), 3.72-3.67 (m,1H), 3.30-3.26 (m, 1H), 3.14-3.07 (m, 1H), 2.07-2.03 (m, 1H), 1.76-1.71(m, 1H), 1.59 (d, 3H), 1.46 (d, 3H), 1.39-1.33(m, 1H), 1.20-1.15 (m,1H), 0.82-0.77 (m, 1H). Peak 2, Example 182,(S)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-olor(R)-1-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol;LCMS m/z = 424 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.16 (s, 1H), 10.75(s, 1H), 8.17 (s, 1H), 7.30 (t, 1H), 5.94 (s, 1H), 5.19 (d, 1H),5.05-5.02 (m, 1H), 4.92-4.85 (m, 1H), 3.90-3.85 (m, 1H), 3.72-3.67 (m,1H), 3.30-3.26 (m, 1H), 3.14-3.07 (m, 1H), 2.07-2.03 (m, 1H), 1.76-1.71(m, 1H), 1.59 (d, 3H), 1.46 (d, 3H), 1.39-1.33(m, 1H), 1.20-1.15 (m,1H), 0.82-0.77 (m, 1H). 31 and 183(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1; RCl:6-chloro-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 165); BrettPhos Pd G4 Isco: SiO₂ (75% EtOAc/PE). SFC:Daicel OX 20 x 250 mm, 10 mm; 25% IPA (0.2% MeOH/NH₃) in CO₂ Peak 1,Example 31,(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine.Peak 2, Example 183,(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine;LCMS m/z = 398 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.21 (br s, 1H),10.85 (br s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.31 (t, 1H), 5.90 (s,1H), 5.40-5.30 (m, 1H), 5.05-4.95 (m, 1H), 4.90-4.85 (m, 1H), 3.88-3.84(m, 1H), 3.72-3.69 (m, 1H), 3.33-3.25 (m, 1H), 3.17-3.12 (m, 1H),2.21-2.18 (m, 1H), 1.77-1.74 (m, 1H), 1.50-1.40 (m, 1H), 1.35-1.25 (m,1H), 0.86-0.83 (m, 1H). 184 and 185(R)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)-5,5-dimethylpyrrolidin-2-oneand(S)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)-5,5-dimethylpyrrolidin-2-one

Amine-1; RCl:3-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)-5,5-dimethylpyrrolidin-2-one(Preparation 166); tBuXPhos Pd G3 prep-HPLC-1; SFC: Daicel OJ 20 x 250mm, 10 mm; 35% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 184,(R)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)-5,5-dimethylpyrrolidin-2-oneor(S)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)-5,5-dimethylpyrrolidin-2-one;LCMS m/z = 393 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.37 (s, 1H), 10.83(s, 1H), 8.19 (d, 2H), 7.94 (s, 1H), 7.31 (t, 1H), 5.86 (s, 1H),4.85-4.70 (m, 1H), 4.54 (dd, 1H), 3.10-3.00 (m, 1H), 1.85 (dd, 1H), 1.70(dd, 1H), 1.11 (s, 3H), 1.01 (s, 3H). Peak 2, Example 185,(S)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)-5,5-dimethylpyrrolidin-2-oneor(R)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)-5,5-dimethylpyrrolidin-2-one;LCMS m/z = 393 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.37 (s, 1H), 10.82(s, 1H), 8.19 (s, 1H), 8.18 (s, 1H), 7.93 (s, 1H), 7.30 (t, 1H), 5.83(s, 1H), 4.80-4.72 (m, 1H), 4.58-4.51 (m, 1H), 3.12-3.03 (m, 1H),1.86-1.82 (m, 1H), 1.71-1.65 (m,1H), 1.10 (s, 3H), 1.00 (s, 3H). 186 and187(S)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3; RCl:6-chloro-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 83); BrettPhos Pd G4 Prep-HPLC-4; SFC: Daicel AD-H 20 x 250mm, 10 mm; 25% IPA (1% NH₃ 7M in MeOH) in CO₂ Peak 1, Example 186,(S)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine;LCMS m/z = 355 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.74 (br s, 1H),10.59 (br s, 1H), 8.56 (dd, 1H), 8.23-8.19 (m, 2H), 7.27-7.25 (m, 1H),6.99-6.97 (m, 1H), 6.37 (br s, 1H,), 5.65 (br s, 1H), 3.80 (s, 3H), 1.94(d, 3H). Peak 2 Example 187,(R)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine;LCMS m/z = 355 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.74 (br s, 1H),10.62 (br s, 1H), 8.60-8.55 (m, 1H), 7.30-7.20 (m, 1H), 6.99 (d, 1H),6.42 (br s, 1H), 5.57 (br s, 1H), 3.80 (s, 3H), 1.94 (d, 3H). 188 and189(S)-1-(1-(4-chloropyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(R)-1-(1-(4-chloropyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-1;6-chloro-1-(1-(4-chloropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 148); BrettPhos Pd G4 prep-HPLC-3; SFC: Daicel OJ 20 x 250mm, 10 mm; 15% MeOH (0.2% DEA in CO₂ Peak 1, Example 188,(S)-1-(1-(4-chloropyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-1-(1-(4-chloropyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine;LCMS m/z = 407 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.31 (br s, 1H),10.85(br s, 1H), 8.52 (d, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.48-7.44 (m,1H), 7.19-7.11 (m, 2H), 6.55-6.52 (m, 1H), 5.84 (s, 1H), 1.93 (d, 3H).Peak 2, Example 189,(R)-1-(1-(4-chloropyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-1-(1-(4-chloropyridin-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine;LCMS m/z = 407 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.32 (br s, 1H),10.80 (br s, 1H), 8.52 (d, 1H), 8.22 (d, 2H), 7.50-7.40 (m, 1H),7.20-7.10 (m, 2H), 6.53 (br s, 1H), 5.85 (br s, 1H), 1.93 (d, 3H). 190and 191(1r,3r)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutane-1-carbonitrileand(1s,3s)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutane-1-carbonitrile

Amine-1;3-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutane-1-carbonitrile(Preparation 175); BrettPhos Pd G4 prep-HPLC-1; SFC: Daicel AD 20 x 250mm, 10 mm; 15% IPA (0.5% MeOH/NH₃) in CO₂ Peak 1, Example 190,(1r,3r)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutane-1-carbonitrileor(1s,3s)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutane-1-carbonitrile;LCMS m/z = 361 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.23 (br s, 1H),10.97 (br s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.31 (t, 1H), 5.93 (s,1H), 4.58 (d, 2H), 3.01-2.90 (m, 1H), 2.36-2.24 (m, 5H). Peak 2, Example191,(1s,3s)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutane-1-carbonitrileor(1r,3r)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutane-1-carbonitrile;LCMS m/z = 361 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.23 (br s, 1H),10.93 (br s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.30 (t, 1H), 5.92 (s,1H,), 4.53 (d, 2H), 3.23-3.18 (m, 1H), 2.85-2.82 (m, 1H), 2.35-2.32 (m,2H), 2.20-2.17 (m, 2H). 192 and 193(R)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(S)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3;6-chloro-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 93); BrettPhos Pd G4 prep-HPLC-3; SFC: Daicel OJ 20 x 250mm, 10 mm; 25% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 192,(R)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine;LCMS m/z = 416 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.75 (br s, 1H),,10.82 (br s, 1H), 8.23 (s, 2H), 6.57 (t, 1H), 5.65-5.45 (br s, 2H),3.80-3.70 (m, 5H), 3.30-3.18 (m, 2H), 1.81 (d, 1H), 1.52-1.25 (m, 3H),1.00 (d, 1H). Peak 2, Example 193,(S)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine;LCMS m/z = 416 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 11.75 (br s, 1H),10.80 (br s, 1H), 8.23-8.21 (m, 2H), 6.56 (t, 1H), 5.54 (br s, 2H),3.89-3.86 (m, 1H), 3.81 (s, 3H), 3.76-3.73 (m, 1H), 3.30-3.18 (m, 2H),1.83-1.79 (m, 1H), 1.48-1.44 (m, 1H), 1.35-1.33 (m, 1H), 1.01-0.98 (m,1H). 194 and 195(R)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineand(S)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Amine-3;6-chloro-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 165); BrettPhos Pd G4 prep-HPLC-1; SFC: Daicel AD 20 x 250mm, 10 mm; 45% MeOH (0.2% MeOH/NH₃) in CO₂ Peak 1, Example 194,(R)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(S)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine;LCMS m/z = 362 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ: 11.66 (br s, 1H),10.67 (br s, 1H), 8.25-8.15 (m, 2H), 5.63-5.53 (m, 1H), 5.41-5.28 (m,1H), 5.05-4.95 (m, 1H), 4.95-4.85 (m, 1H), 3.90-3.83 (m, 1H), 3.82 (s,3H), 3.75-3.70 (m, 1H), 3.31-3.25 (m, 1H), 3.19-3.12 (m, 1H), 2.28-2.23(m, 1H), 1.76-1.71 (m, 1H), 1.51-1.42 (m, 1H), 1.28-1.23 (m, 1H),0.88-0.83 (m, 1H). Peak 2, Example 195,(S)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor(R)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine;LCMS m/z = 362 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ: 11.67 (br s, 1H),10.66 (br s, 1H), 8.20 (s, 2H), 5.64 (br s, 1H), 5.29 (br s, 1H),5.10-4.85 (m, 2H), 3.90-3.70 (m, 5H), 3.50 (t, 1H), 3.16 (t, 1H),2.40-2.20 (m, 1H), 1.75 (d, 1H), 1.44 (q, 1H), 1.26 (q, 1H), 0.88 (d,1H). 196 and 197(1S,2S)-2-((6-((5-methoxy-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrileand(1R,2R)-2-((6-((5-methoxy-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile

Amine-3;trans-rac-2-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile(Preparation 94); BrettPhos Pd G4 prep-HPLC-1; SFC: Daicel OD 20 x 250mm, 10 mm; 20% MeOH (0.2% DEA) in CO₂ Peak 1, Example 196,(1S,2S)-2-((6-((5-methoxy-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrileor(1R,2R)-2-((6-((5-methoxy-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile;LCMS m/z = 311 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ: 11.69 (br s, 1H),10.63 (br s, 1H), 8.20 (s, 1H), 5.61 (br s, 1H), 4.46 (br s, 2H), 3.83(s, 3H), 2.05-1.95 (m, 1H), 1.90-1.85 (m, 1H), 1.30-1.18 (m, 2H). Peak2, Example 197,(1R,2R)-2-((6-((5-methoxy-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrileor(1S,2S)-2-((6-((5-methoxy-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile;LCMS m/z = 311 [M+H]+; 1H NMR (400 MHz, DMSO-d₆) δ: 11.78 (br s, 1H),10.68 (br s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 5.70 (br s, 1H), 4.45 (d,2H), 3.82 (s, 3H), 2.01-1.95 (m, 1H), 1.89-1.84 (m, 1H), 1.31-1.27 (m,1H), 1.21-1.16 (m, 2H).

Example 198(R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropan-1-ol

Part 1. A mixture of methyl(R)-3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate(Preparation 95, 100 mg, 0.39 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (59 mg, 0.39 mmol), t-BuXphos PdG3 (31 mg, 0.04 mmol) and KOAc (98 mg, 1.0 mmol) in dioxane (3 mL) wasstirred at 100° C. for 3h under N₂. The reaction mixture was cooled tort and concentrated to give a residue which was purified by flash columnchromatography (SiO₂, 0-75% EtOAc/PE) to give(R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate(80 mg, 56%). LCMS m/z = 368 [M+H]⁺

Part 2. LiAlH₄ (17 mg, 0.45 mmol) was added to a solution of(R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate(Part 1, 80 mg, 0.22 mmol) in THF (5 mL) at 0° C., then stirred for 5 hat 20° C. The reaction mixture was quenched with MeOH (5 drops) thenconcentrated in vacuo. The residue was purified by flash chromatography(SiO2, 30-90% EtOAc/PE) followed by prep-HPLC-1 to give the titlecompound as a yellow solid (30 mg, 41%). LCMS m/z = 340 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) δ: 12.31 (br s, 1H), 10.82 (br s, 1H), 8.19 (s, 1H),8.15 (s, 1H), 7.29 (t, 1H), 5.93 (s, 1H), 4.90 (s, 1H), 4.44-4.30 (m,2H), 3.39-3.27 (m, 2H), 2.19-2.12 (m, 1H), 0.81 (d, 3H).

Example 199(S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropan-1-ol

The title compound was prepared from methyl(S)-3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate(Preparation 105) and 5-(difluoromethoxy)-1H-pyrazol-3-amine using ananalogous 2-part procedure as described for Example 198. Purified byprep-HPLC-5 to afford the title compound (46.4 mg, 34%). LCMS m/z = 340[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.17 (s, 1H), 8.13 (s, 1H), 7.28(t, 1H), 5.95 (s, 1H), 4.43-4.29 (m, 2H), 3.30-3.26 (m, 2H), 2.16-2.13(m, 1H), 0.81 (d, 3H).

Example 200(S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(piperidin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Part 1. A mixture of tert-butyl(S)-3-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate(Preparation 104, 300 mg, 0.85 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (190 mg, 1.28 mmol), BrettPhos PdG4 (20 mg, 0.21 mmol) and KOAc (251 mg, 2.56 mmol) in dioxane (5 mL) wasstirred at 90° C. overnight under N₂. The reaction mixture was cooled tort and concentrated to give a residue which was purified by flash columnchromatography (SiO2, 80% EtOAc/PE) to give tert-butyl(S)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate(250 mg, 63%). LCMS m/z = 413 [M+H]⁺

Part 2. To a solution of tert-butyl(S)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate(Part 1, 250 mg, 0.53 mmol) in THF (20 mL) was added TFA (0.5 mL) at 25°C. and the resulting mixture stirred for 2 h at rt. The reaction mixturewas evaporated to dryness in vacuo and the residue was purified byprep-HPLC-4 to afford the title compound (24.4 mg, 12%). LCMS m/z = 365[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16 (s, 1H), 8.11 (s, 1H), 7.27(t, 1H), 6.15-6.12 (m, 1H), 4.58-3.97 (m, 2H), 2.80-2.60 (m, 1H),2.49-2.23 (m, 3H), 1.77-1.52 (m, 2H), 1.45-1.32 (m, 2H), 1.20-1.12 (m,1H).

Example 201 and 202(2R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-oland(2R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol

To a solutionN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(Preparation 188, 250 mg, 0.53 mmol) in THF (20 mL) was added TFA (0.5mL) at 25° C. and the resulting reaction mixture was stirred for 2 h atrt. The reaction mixture was evaporated to dryness in vacuo and theresidue was purified by prep-HPLC-4 to give a mixture of title compounds(16.0 mg, 12%). The mixture was separated by chiral-SFC (Daicel IC,20 x250 mm, 10 mm; 30% MeOH (0.2% MeOH/NH3) in CO2 to afford the titlecompounds.

Peak 1, Example 201,(2R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-olor(2R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol(8 mg): LCMS m/z = 354 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ: 12.18 (br s,1H), 10.91 (br s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.31 (t, 1H),6.01-5.99 (m, 1H), 5.06 (d, 1H), 4.60-4.53 (m, 1H), 4.02-3.98 (m, 1H),2.14-1.99 (m, 2H), 0.79 (d, 3H), 0.61 (t, 3H).

Peak 2, Example 202,(2R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-oland(2R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol,White solid (8 mg): LCMS m/z = 354 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:12.18 (br s, 1H), 10.91 (br s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.31 (t,1H), 6.00 (br s, 1H), 5.06 (d, 1H), 4.70-4.60 (m, 1H), 4.05-3.95 (m,1H), 2.25-1.90 (m, 2H), 0.79 (d, 3H), 0.61 (t, 3H).

Example 203(R)-2-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-phenylethan-1-ol

Part 1. A mixture of(R)-6-chloro-1-(1-phenyl-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 130, 700 mg, 1.62 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (363 mg, 2.44 mmol), BrettPhos PdG4 (20 mg, 0.21 mmol) and KOAc (478 mg, 4.87 mmol) in dioxane (20 mL)was stirred at 90° C. overnight under N₂. The reaction mixture wascooled to rt and concentrated in vacuo to give a residue which waspurified by flash column chromatography (SiO₂, 66% EtOAc/PE) to afford(R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-phenyl-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineas a yellow solid (260 mg, 29%). LCMS m/z = 544 [M+H]⁺.

Part 2. The compound of Part 1 (250 mg, 0.20 mmol) in TBAF/THF (3 mL)was stirred at rt overnight. The reaction mixture was evaporated todryness and the residue purified by prep-HPLC-4 to afford the titlecompound as a white solid (116 mg, 62%). LCMS m/z = 388 [M+H]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ: 12.21 (br s, 1H), 10.77 (br s, 1H), 8.22 (s, 1H),8.20 (s, 1H), 7.43-7.23 (m, 5H), 7.31 (t, 1H), 6.23-6.19 (m, 1H), 6.01(br s, 1H), 5.03 (t, 1H), 4.40-4.35 (m, 1H), 4.08-4.01 (m, 1H).

Example 204(R)-2-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-(pyridin-3-yl)ethan-1-ol

The title compound was prepared from(R)-6-chloro-1-(1-(pyridin-3-yl)-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 137) and 5-(difluoromethoxy)-1H-pyrazol-3-amine using ananalogous 2-part method as described for Example 203. Purification byprep-HPLC-1 afforded the title compound as white solid (78.8 mg, 45%).LCMS m/z = 389 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.28 (s, 1H), 10.83(s, 1H), 8.68 (d, 1H), 8.48 (dd, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 7.85(d, 1H), 7.35 (dd, 1H), 7.32 (t, 1H), 6.39-6.35 (m, 1H), 5.94 (s, 1H),5.14 (t, 1H), 4.33-4.30 (m, 1H), 4.14-4.08 (m, 1H).

Example 205 and 206(S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)butan-1-oland(R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)butan-1-ol

The title compound was prepared from6-chloro-1-(4-((triisopropylsilyl)oxy)butan-2-yl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 167) and 5-(difluoromethoxy)-1H-pyrazol-3-amine using ananalogous 2-part method as described for Example 203. prep-HPLC-1followed by prep-SFC (Daicel OZ20 x 250 mm, 10 mm; 20% MeOH (0.2%MeOH/NH₃) in CO₂.

Peak 1, Example 205,(S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)butan-1-olor(R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-bipyrazin-1-yl)butan-1-ol,white solid; LCMS m/z = 340 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ: 12.23(br s, 1H), 10.79 (br s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.29 (t, 1H),5.96 (s, 1H), 5.25-5.19 (m, 1H), 4.66-4.60 (m, 1H), 3.33-3.24 (m, 1H),3.18-3.10 (m, 1H), 2.06-1.90 (m, 2H), 1.49 (d, 3H).

Peak 2, Example 206,(R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)butan-1-olor(S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)butan-1-ol,white solid; LCMS m/z = 340 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.22(s, 1H), 10.77 (s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.29 (t, 1H), 5.95(s, 1H), 5.25-5.19 (m, 1H), 3.33-3.24 (m, 1H), 3.18-3.10 (m, 1H),2.06-1.90 (m, 2H), 1.49 (d, 3H).

Example 207, 208, 209 and 210(1S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo|3,4-bipyrazin-1-yl)cyclopentan-1-ol and(1R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-bipyrazin-1-yl)cyclopentan-1-oland(1R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-bipyrazin-1-yl)cyclopentan-1-oland(1S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol

Part 1. A mixture of3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol (Preparation132, 200 mg, 0.837 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (124mg, 0.837 mmol), t-BuXPhos Pd G3 (66.5 mg, 0.0837 mmol) and KOAc (246mg, 2.51 mmol) in dioxane (10 mL) was degassed with N2 (3x), and thenheated at 100oC for 3 hunder N2. The reaction mixture was cooled to rtand concentrated to give a residue which was purified by flash columnchromatography on silica gel (80% EtOAc/PE) to give a residue that wasfurther purified prep-HPLC-3 to give Intermediate Product 1 (150 mg,50%) and Intermediate Product 2 (50 mg, 16%).

Part 2. Intermediate Product 1 was further purified by chiral-SFC(Daicel IG, 20 x 250 mm, 10 mm; 25% MeOH (0.2% MeOH/NH3) in CO2 to givePeak 1 and Peak 2 as yellow solids.

Peak 1, Example 207,(1S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor(1R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor(1R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor (1S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol(51.4 mg); LCMS m/z = 352 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.27 (s,1H), 10.74 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.31 (t, 1H), 5.93 (s,1H), 5.67-5.63 (m, 1H), 4.74 (d, 1H), 4.43-4.40 (m,1H), 2.34-2.25 (m,1H), 2.23-2.15 (m, 1H), 2.15-2.01 (m, 2H), 1.95-1.90 (m, 1H), 1.65-1.60(m, 1H).

Peak 2, Example 208,(1R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor(1S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor(1R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor (1S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol(63 mg); LCMS m/z = 352 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.27 (s,1H), 10.74 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.31 (t, 1H), 5.93 (s,1H), 5.67-5.63 (m, 1H), 4.74 (d, 1H), 4.43-4.40 (m,1H), 2.34-2.25 (m,1H), 2.23-2.15 (m, 1H), 2.15-2.01 (m, 2H), 1.95-1.90 (m, 1H), 1.65-1.60(m, 1H).

Part 3. Intermediate Product 2 was further purified by chiral-SFC(Daicel IG, 20 x 250 mm, 10 mm; 20% MeOH (0.2% MeOH/NH3) in CO2 to givePeak 3 and Peak 4 as yellow solids.

Peak 3, Example 209,(1R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor(1S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor(1S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor(1R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol(16.7 mg); LCMS m/z = 352 [M+H]+; ¹H NMR (400 MHz, DMSO-d6) δ: 12.25 (brs, 1H), 10.95 (br s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.31 (t, 1H), 5.89(s, 1H), 5.37 (m, 1H), 4.99 (s, 1H), 4.25 (s, 1H), 2.42 (m, 1H), 2.20(m, 1H), 2.03 (m, 2H), 1.80 (m, 2H).

Peak 4, Example 210,(1S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor(1R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor(1S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-olor(1R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol(17.4 mg); LCMS m/z = 352 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.25 (brs, 1H), 10.95 (br s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.31 (t, 1H), 5.89(s, 1H), 5.37 (s, 1H), 4.99 (s, 1H), 4.25 (s, 1H), 2.42 (m, 1H), 2.20(m, 1H), 2.03 (m, 2H), 1.80 (m, 2H).

Example 211, 212, 213 and 2141-((S)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-blpyrazin-6-amineand1-((S)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-IH-pyrazol-3-yl)-1H-pyrazolo[3,4-blpyrazin-6-amineand1-((R)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-blpyrazin-6-amineand1-((R)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

Part 1. A mixture oftrans-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazineor cis-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (Product 1, Preparation 183 and 184,100 mg, 0.37 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (75 mg, 0.5mmol), BrettPhos Pd G4 (92 mg, 0.1 mmol) and KOAc (80 mg, 0.8 mmol) indioxane (3 mL) was stirred at 100 oC for 2 h under N2. The reactionmixture was cooled to rt and evaporated to dryness in vacuo to afford aresidue that was purified by flash column chromatography on silica gel(10:1 PE/EtOAc) to give Intermediate Product A as a yellow solid (50 mg,35%). LCMS m/z = 382 [M+H]+.

Part 2. Intermediate Product B (yellow solid, 210 mg, 42%) was preparedfrom a mixture ofcis-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazineor trans-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (Product 2, Preparation 183 and 184)and 5-(difluoromethoxy)-1H-pyrazol-3-amine using an analogous method tothat described in Part 1 above. LCMS m/z = 382 [M+H]+.

Part 3. Intermediate Product A (Part 1) was separated by chiral-SFC(Daicel OJ, 20 × 250 mm, 10 mm; 15% MeOH (0.2% MeOH/NH3) in CO2 toafford:

Peak 1, Example 211,1-((S)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((R)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((S)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((R)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(15.2 mg); LCMS m/z = 382 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.31 (brs, 1H), 10.88 (br s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.31 (t, 1H), 5.95(s, 1H), 5.18 (s, 1H), 3.89-3.81 (m, 2H), 3.67-3.58 (m, 2H), 3.45-3.38(m, 1H), 3.27-3.20 (m, 1H), 3.14-3.09 (m, 1H), 1.53 (d, 3H).

Peak 2, Example 212,1-((R)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((S)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((S)-1-((R)-,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((R)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(44.9 mg); LCMS m/z = 382 [M+H]+; ¹H NMR (400 MHz, DMSO-d6) δ: 12.31 (brs, 1H), 10.88 (br s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.31 (t, 1H), 5.95(s, 1H), 5.18 (s, 1H), 3.89-3.81 (m, 2H), 3.67-3.58 (m, 2H), 3.45-3.38(m, 1H), 3.27-3.20 (m, 1H), 3.14-3.09 (m, 1H), 1.53 (d, 3H).

Part 4. Intermediate Product B (Part 2) was separated by chiral-SFC(Daicel OJ, 20 x 250 mm, 10 mm; 15% MeOH (0.2% MeOH/NH3) in CO2 toafford:

Peak 3, Example 213,1-((S)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((R)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((R)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((S)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(15.2 mg); LCMS m/z = 382 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.27 (brs, 1H), 10.83 (br s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.31 (t, 1H), 5.92(s, 1H), 5.20 (s, 1H), 3.94-3.90 (m, 2H), 3.63-3.56 (m, 2H), 3.40-3.31(m, 3H), 1.41 (d, 3H).

Peak 4, Example 214,1-((R)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((S)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((R)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amineor1-((S)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(15.2 mg); LCMS m/z = 382 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆) δ: 12.27 (brs, 1H), 10.83 (br s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.31 (t, 1H), 5.92(s, 1H), 5.20 (s, 1H), 3.94-3.90 (m, 2H), 3.63-3.56 (m, 2H), 3.40-3.31(m, 3H), 1.41 (d, 3H).

Example 215, 216, 217 and 218N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-bipyrazin-6-amineandN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-bipyrazin-6-amineandN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-bipyrazin-6-amineandN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-IH-pyrazolo[3,4-blpyrazin-6-amine

Part 1. To a solution of6-chloro-1-(1-(tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine(Preparation 89, 300 mg, 1.12 mmol) and5-(difluoromethoxy)-1H-pyrazol-3-amine (250 mg, 1.68 mmol) in dioxane(10 mL) was added tBuXPhos Pd G3 (177 mg, 0.224 mmol) and KOAc (219 mg,2.24 mmol) at ambient temperature and the resulting mixture was purgedwith N₂ and then stirred at 100° C. for 2 h. The reaction mixture wasevaporated to dryness and the residue purified by prep-HPLC-1 to giveN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineas a white solid (44 mg, 10%). LCMS m/z = 380 [M+H]+.

Part 2.N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(Part 1) was further purified by chiral-SFC (Daicel OJ; 20 x 250 mm, 10mm; 15% MeOH (0.2% MeOH/NH3) in CO2 to afford the title compounds. LCMSm/z = 380 [M+H]+

Peak 1, Example 215,N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(0.9 mg): ¹H NMR (400 MHz, DMSO-d6) δ: 12.19 (s, 1H), 10.76 (s, 1H),8.20 (s, 1H), 8.17 (s, 1H), 7.30 (t, 1H), 5.97 (s, 1H), 5.05-5.01 (m,1H), 3.96 (dd, 1H), 3.67 (d, 1H), 3.32-3.21 (m, 2H), 2.07-2.05 (m, 1H),1.46 (d, 3H), 1.35-1.23 (m, 2H), 1.15-1.12 (m, 1H), 1.05-0.99 (m, 1H).

Peak 2, Example 216,N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)--((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(2.8 mg): ¹H NMR (400 MHz, DMSO-d₆) δ: 12.40-12.30 (br, 1H), 10.95-10.72(br, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.30 (t, 1H), 5.97 (s, 1H),5.05-5.01 (m, 1H), 3.96 (dd, 1H), 3.68 (dd, 1H), 3.32-3.21 (m, 2H),2.07-2.05 (m, 1H), 1.46 (d, 3H), 1.35-1.23 (m, 2H), 1.15-1.12 (m, 1H),1.05-0.99 (m, 1H).

Peak 3, Example 217,N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(3.5 mg): ¹H NMR (400 MHz, DMSO-d₆) δ: 12.40-12.30 (br s, 1H),10.95-10.72 (br s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.30 (t, 1H), 5.97(s, 1H), 5.02-4.95 (m, 1H), 3.69 (d, 1H), 3.32-3.23 (m, 1H), 3.15-3.12(m, 1H), 3.02-2.96 (m, 1H), 2.13-2.10 (m, 1H), 1.98-1.95 (m, 1H),1.66-1.60 (m, 1H), 1.53 (d, 3H), 1.48-1.33 (m, 2H).

Peak 4, Example 218,N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amineorN-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(5.6 mg): ¹H NMR (400 MHz, DMSO-d₆) δ: 12.19 (s, 1H), 10.80 (s, 1H),8.20 (s, 1H), 8.17 (s, 1H), 7.31 (t, 1H), 5.97 (s, 1H), 4.99 (s, 1H),3.70-3.68 (m, 1H), 3.32-3.23 (m, 1H), 3.15-3.12 (m, 1H), 3.02-2.96 (m,1H), 2.13-2.10 (m, 1H), 1.98-1.95 (m, 1H), 1.66-1.60 (m, 1H), 1.53 (d,3H), 1.48-1.33 (m, 2H).

Example 219(3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-blpyrazin-1-yl)cyclobutyl)methanol

Part 1. A mixture of1-(3-((benzyloxy)methyl)cyclobutyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Preparation 176, 410 mg, 1.24 mmol),5-(difluoromethoxy)-1H-pyrazol-3-amine (184 mg, 1.24 mmol), KOAc (364mg, 3.72 mmol) and BrettPhos Pd G4 (114 mg, 0.124 mmol) in dioxane (12mL) was stirred at 90° C. for 14h under N₂. The reaction mixture wasconcentrated in vacuo and the residue purified by flash chromatographyon silica gel (33% EtOAc/PE) to give1-(3-((benzyloxy)methyl)cyclobutyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (230 mg, 42%) as a white solid.LCMS m/z = 442 [M+H]+.

Part 2. A mixture of1-(3-((benzyloxy)methyl)cyclobutyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (Part 1, 200 mg, 0.453 mmol) andPd/C (10% wet, 80 mg) in EtOAc (18 mL) was stirred at ambienttemperature under H2 for 14h. The reaction mixture was filtered througha pad of Celite®. The filtrate was concentrated and the residue purifiedby prep-HPLC-2 to afford the title compound as a white solid (59 mg,37%). LCMS m/z = 352 [M+H]+; ¹H NMR (400 MHz, DMSO-d6) δ: 12.26 (br s,1H), 10.75 (br s, 1H), 8.20 (s, 1H), 8.18 (s, 1H), 7.31 (t, 1H), 5.92(s, 1H), 5.63 (s, 1H), 4.73 (t, 1H), 3.64-3.61 (m, 2H), 2.69-2.67 (m,3H), 2.30-2.25 (m, 2H).

Example 220(1r,3r)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-bipyrazin-1-yl)methyl)cyclobutan-1-ol

To a solution of1-(((1r,3r)-3-(benzyloxy)cyclobutyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine(Preparation 191, 350 mg, 0.792 mmol) in MeOH (10 mL) at 25° C. wasadded Pd/C (200 mg) and the mixture stirred under H₂ for 1 h. Thereaction mixture was filtered and the filtrate was concentrated to givea residue which was purified by prep-HPLC-3 to afford the title compoundas a yellow solid (66.6 mg, 23%). LCMS m/z = 352 [M+H]+; ¹H NMR (400MHz, DMSO-d₆) δ: 11.70-10.85 (m, 2H), 8.18 (s, 1H), 8.12 (s, 1H), 7.30(t, 1H), 6.01 (s, 1H), 5.01-4.93 (m, 1H), 4.50 (d, 2H), 4.28-4.21 (m,1H), 2.68-2.60 (m, 1H), 2.09-2.01 (m, 2H), 1.93-1.86 (m, 2H).

Example 2211-(3-oxabicyclo[3.1.0]hexan-1-ylmethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolor3,4-blpyrazin-6-amine

Part 1: 3-oxabicyclo[3.1.0]hexan-1-ylmethanol (85.5 mg, 0.75 mmol) and6-chloro-1H-pyrazolo[3,4-b]pyrazine (77.0 mg, 0.50 mmol) were dissolvedin THF (6 mL) and DIAD (121.2 mg, 0.60 mmol) and triphenylphosphineresin (83.3 mg, 3.0 mmol/g, 0.25 mmol) were added under N₂ and thereaction mixture was shaken at 30° C. for 16 h. The reaction mixture wasfiltered and the filtrate concentrated under reduced pressure. Theresidue was diluted with EtOAc (5 mL) and partitioned between EtOAc (5mL) and H2O (5 mL). The combined organics were washed (2x 2.5 mL), dried(Na2SO4) and concentrated under reduced pressure to afford1-(3-oxabicyclo[3.1.0]hexan-1-ylmethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazinewas used in Part 2 without further purification.

Part 2. A mixture of tert-butyl3-amino-5-(difluoromethoxy)-1H-pyrazole-1-carboxylate (Preparation 30,99.6 mg, 0.40 mmol),1-(3-oxabicyclo[3.1.0]hexan-1-ylmethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine(Part 1, 0.40 mmol), K3PO4 (253.2 mg, 1.20 mmol) and XantPhos Pd G3(19.0 mg, 0.015 mmol) were combined in t-AmOH (5 mL) at rt under N2 andthe resulting mixture stirred at 100° C. for 2 h under N2. The reactionmixture was diluted with EtOAc (5 mL) and washed with water (3x 5 mL).The combined organics were dried (Na2SO4) and evaporated to affordtert-butyl3-((1-(3-oxabicyclo[3.1.0]hexan-1-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)amino)-5-(difluoromethoxy)-1H-pyrazole-1-carboxylatewas used in Part 3 without further purification.

Part 3. tert-butyl3-((1-(3-oxabicyclo[3.1.0]hexan-1-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)amino)-5-(difluoromethoxy)-1H-pyrazole-1-carboxylate(Part 2, 0.30 mmol) was dissolved in DCM (1.5 mL) and HCl-Dioxane (1.5mL, 4 M) was added at rt and the resulting mixture stirred at 30° C. for2 h. The mixture was concentrated under reduced pressure and the residuewas purified by prep-HPLC to afford the title compound (10.8 mg, 6%).LCMS m/z = 364 [M+H]+;

Example 222N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(pyridazin-3-ylmethyl)-1H-pyrazolo[3,4-blpyrazin-6-amine

The title compound (13.9, 8%) was prepared from pyridazin-3-ylmethanol,6-chloro-1H-pyrazolo[3,4-b]pyrazine and tert-butyl3-amino-5-(difluoromethoxy)-1H-pyrazole-1-carboxylate (Preparation 30)using an analogous 3-part protocol as described for Example 221. LCMSm/z = 360 [M+H]+.

Example 223N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(pyrazin-2-ylmethyl)-1H-pyrazolo[3,4-blpyrazin-6-amine

The title compound (12.4 mg, 7%) was prepared from pyrazin-2-ylmethanol,6-chloro-1H-pyrazolo[3,4-b]pyrazine and tert-butyl3-amino-5-(difluoromethoxy)-1H-pyrazole-1-carboxylate (Preparation 30)using an analogous 3-part protocol as described for Example 221. LCMSm/z = 360 [M+H]+.

Example 224N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(pyridin-3-ylmethyl-d2)-1H-pyrazolo[3,4-blpyrazin-6-amine

Part 1: A solution of nicotinic acid (1.33 g, 10.8 mmol) in THF wasadded LiAlD₄ (0.5 g, 11.9 mmol) at 0° C., and stirred RT for 15 h. D20(0.5 mL) was added and then 15% NaOD in D₂O (0.5 mL) was added, then D20(1.5 mL) was added. Filtered and the filtrate was concentrated to givepyridin-3-ylmethan-d2-ol (0.84 g, 70%) as a light yellow oil. MS (ES+)C₆H₅D₂NO requires: 111, found: 112 [M+H]⁺

Part 2: To a stirred solution of pyridin-3-ylmethan-d2-ol (Part 1, 200mg, 1.79 mmol), 6-chloro-1H-pyrazolo[3,4-b]pyrazine (276 mg, 1.79 mmol)and PPh3 (541 mg, 2.68 mmol) in THF (10 mL) was added DIAD (937 mg, 3.58mmol) at 0° C. under nitrogen atmosphere. The resulting mixture wasstirred for 2 h at room temperature under N₂. The reaction mixture wasconcentrated and the residue was purified by silica gel columnchromatography eluting with PE/EA (10:1 to 5:1) to afford6-chloro-1-(pyridin-3-ylmethyl-d2)-1H-pyrazolo[3,4-b]pyrazine (210 mg,47% yield) as a light yellow oil. MS (ES+) C11H6D2ClN5 requires: 247,found: 248 [M+H]+.

Part 3: A mixture of6-chloro-1-(pyridin-3-ylmethyl-d2)-1H-pyrazolo[3,4-b]pyrazine (Part 2,210 mg, 847 pmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (126 mg, 847pmol), KOAc (248 mg, 2.54 mmol) and Brett Phos Pd G4 (40 mg) in Dioxane(6 mL) was stirred at 100° C. under N2 for 2 h. The reaction mixture wasconcentrated and the residue was purified by silica gel columnchromatography eluting with PE/EA (2: 1 to 1:1) to afford the crudeproduct (180 mg). The crude product was purified by Prep-HPLC (Mobilephase: A = water(0.1% NH4HCQ3), B = acetonitrile; Gradient: B = 15%-95%in 18 min; Column: Xtimate 10 um 150A 21.2×250 mm) to obtain the titleproduct (145.7 mg, 47.5% yield) as a white solid. MS (ES+) C15H10D2F2N8Orequires: 360, found: 361 [M+H]+.1H-NMR (400 MHz, DMSO-d6) δ ppm 12.31(s, 1H), 10.88 (s, 1H), 8.57 (s, 1H), 8.47 (d, J = 4.8 Hz, 1H),8.21-8.19 (m, 2H), 7.67-7.64 (m, 1H), 7.50-7.12 (m, 2H), 5.88 (s, 1H)

Example 225 N-( difluoromethoxy)-1H-pyrazol-3-yl)-1-( ethyl-I, 1-d2)-1H-pyrazolor3,4-blpyrazin-6-amine

The title compound (49 mg, 30%) was prepared from1-hydroxyethane-1,1-d2, chloro-1H-pyrazolo[3,4-b]pyrazine and5-(difluoromethoxy)-1H-pyrazol-3-amine following an analogous 3-partprotocol as described in Example 224. MS (ES+) C11H9D2F2N70 requires:297, found: 298 [M+H]+.1H-NMR (400 MHz, DMSO-d6) δ ppm 12.21 (s, 1H),10.72 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 7.32 (t, J = 73.6 Hz, 1H),5.91 (s, 1H), 1.34 (s, 3H).

Example 226N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl-d2)-1H-pyrazolo[3,4-bipyrazin-6-amine

The title compound (86.9 mg, 23%) was prepared from methyltetrahydro-2H-pyran-4-carboxylate, chloro-1H-pyrazolo[3,4-b]pyrazine and5-(difluoromethoxy)-1H-pyrazol-3-amine using an analogous 3-partprotocol as described for example 224. MS (ES+) C₁₅H₁₅D₂F₂N70₂ requires:367, found: 368[M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 11.21 (br. s.,1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.32 (t, J = 73.6 Hz, 1H), 6.01 (s,1H), 3.83-3.79 (m, 2H), 3.25-3.19 (m, 2H), 2.17-2.12 (m, 1H), 1.40-1.30(m, 4H).

Example 227N-(5-(methoxy-d3)-1H-pyrazol-3-yl)-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4₋blpyrazin-6-amine

Part 1: To a mixture of methan-d3-ol-d (1.0 g, 27.7 mmol) andtriethylamine (5.6 g, 55.4 mmol) in DCM (10 mL) was added dropwiseMethanesulfonyl chloride (3.1 g, 27.7 mmol) at 0° C., then stirred at rtfor 1h. The reaction was diluted with DCM and washed with water andbrine. The organic layer was concentrated. The residue was used to thenext step directly (Part 3).

Part 2: A mixture of 5-amino-2,4-dihydro-3H-pyrazol-3-one (11.0 g, 0.11mol) and isobenzofuran-1,3-dione (17.0 g, 0.11 mol) in HOAc (200 mL) wasstirred for 2 h at 120 oC. The reaction mixture was cooled to rt. Theprecipitate was collected by filtration to give2-(5-oxo-4,5-dihydro-1H-pyrazol-3-yl)isoindoline-1,3-dione (20.0 g,yield 80 %) as a gray solid. MS (ES+) C11H7N303 requires: 229, found:230 [M+H]+.

Part 3: A mixture of2-(5-oxo-4,5-dihydro-1H-pyrazol-3-yl)isoindoline-1,3-dione (Part 2, 1.0g, 4.36 mmol), methyl-d3 methanesulfonate (Part 1, 1.2 g, 8.72 mmol) andK2CO3 (493 mg, 4.36 mmol) in DMF (10 mL) was stirred at 35° C.overnight. The reaction mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was purified by flashchromatography on silica gel eluting with DCM/MeOH = 4:1 to give2-(5-(methoxy-d3)-1H-pyrazol-3-yl)isoindoline-1,3-dione (2.8 g, crudeproduct) as a yellow oil. MS (ES+) C12H6D3N3O3 requires: 246, found: 247[M+H]+.

Part 4: A mixture of2-(5-(methoxy-d3)-1H-pyrazol-3-yl)isoindoline-1,3-dione (Part 3, 2.8 g,crude) in EtOH (6 mL) was added hydrazine hydrate (2 mL), then stirredat 70° C. for 2 h. The reaction mixture was purified by flashchromatography on silica gel eluting with DCM/MeOH = 2:1 to yield5-(methoxy-d3)-1H-pyrazol-3-amine (0.8 g) as a yellow oil. MS (ES+)C4H4D3N3O requires: 116, found: 117 [M+H]+.

Part 5: A mixture of methyl6-chloro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation35, 400 mg, 1.63 mmol), 5-(methoxy-d3)-1H-pyrazol-3-amine (Part 4, 0.8g, crude), BrettPhos Pd G4 (24 mg, 0.24 mmol) and potassium acetate (479mg, 4.89 mmol) in dioxane (10 mL) was stirred at 90 oC for overnightunder N2. The reaction mixture was cooled to RT and concentrated. Theresidue was purified by Prep-HPLC (Mobile phase: A = water(0.1%NH₄HCO₃), B = acetonitrile; Gradient: B = 15%-95% in 18 min; Column:Xtimate 10 um 150A 21.2×250mm) to give the title product (19.9 mg, 4%yield). MS (ES+) C15H11D3N8O requires: 325, found: 326 [M+H]+.1H-NMR(400 MHz, DMSO-d6) δ ppm 11.79 (br.s, 1H), 10.67 (br.s, 1H), 8.58 (s,1H), 8.47 (d, J = 4.0 Hz, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.64 (d, J =7.6 Hz, 1H), 7.34 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 5.75 (s, 2H), 5.59 (br.s, 1H).

Biological Example 1

Inhibitory effects of the compounds of the disclosure were measured inbiochemical assays that measure the enzymatic phosphorylation activityof CDK enzyme in complex of Cyclin proteins phosphorylates 7.5micromolar fluorescently labelled peptide substrate, 5-FAM-QSPKKG-CONH2,(FL-Peptide 18, Perkin Elmer, 760362) in the presence ofadenosine-5′-triphosphate (ATP) and varying concentrations of the testcompound in 100 mM 2-[4-(2-hydroxyethyl)piperazin-1-yl] ethanesulfonicacid (HEPES), pH 7.5, 10 mM MgCl₂, 0.015% Brij-35, 1 mM dithiothreitol(DTT), 1.0% dimehylsulfoxide (DMSO). Assays were performed at 1.0 mM ATPor at ATP Km of the CDK enzymes in complex with Cyclin proteins.Reactions proceeded until between 10% to 20% total peptides werephosphorylated at room temperature (25° C.) and were terminated with 35mM 2,2′,2′′,2‴-(ethane-1,2-diyldinitrilo)tetraacetic acid (EDTA).Product was detected using the Caliper mobility shift detection methodwhere the phosphorylated peptide (product) and substrate wereelectrophoretically separated and measured. Percent activity was plottedagainst log concentration of compound and points to generate an apparentIC₅₀. The following CDK enzymes in complex with different cyclinproteins were used in these assays:

-   CDK1/Cyclin B1,GST-tag (BPS, 40454), 1.5 nM used in the assay-   CDK2/Cyclin E (Eurofins, 14-475), 1.25 nM used in the assays

Biological assay data of the test compounds are provided in Table 1below. For inhibitory activity against CDK2/Cyclin E mutant, thefollowing designations are used: ≤ 10 nM = A; >10-20 nM = B; >20-30 nM =C; >30 - 100 nM = D and >100 = E. For inhibition CDK1/Cyclin B1,GST-tag:≥ 500 nM = A; <100-500 nM = B; < 100 nM = C.

TABLE 1 Tabularized Data Example Number CDK2/ cyclin E1 IC50 (nM) CDK1/cyclin B1 IC50 (nM) 1 A B 2 A B 3 A B 4 A A 5 A A 6 D A 7 A B 8 A C 9 AA 10 A C 11 C A 12 D A 13 A C 14 B A 15 D A 16 A A 17 A B 18 C A 19 A B20 A A 21 C A 22 A B 23 A B 24 A B 25 D A 26 E A 27 A B 28 C A 29 A A 30C A 31 A C 32 C A 33 A B 34 B A 35 A A 36 C A 37 C A 38 A B 39 C A 40 BA 41 A A 42 C A 43 A A 44 B A 45 A A 46 A A 47 A A 48 A A 49 A B 50 A A51 A B 52 D A 53 A A 54 D A 55 A A 56 B A 57 D A 58 A A 59 A A 60 A A 61A A 62 A A 63 A B 64 C A 65 A C 66 A C 67 A A 68 B A 69 D A 70 A B 71 BA 72 A A 73 B A 74 C A 75 C A 76 C A 77 A B 78 D A 79 C A 80 A A 81 A A82 C A 83 A A 84 A A 85 B A 86 A A 87 A B 88 A A 89 A A 90 D A 91 C A 92A A 93 A A 94 A A 95 C A 96 D A 97 A A 98 B A 99 A A 100 B A 101 A B 102C A 103 C A 104 A B 105 A B 106 A B 107 C A 108 A A 109 A B 110 A B 111A A 112 C A 113 D A 114 A B 115 D A 116 A A 117 A B 118 A B 119 A A 120A A 121 D A 122 C A 123 A A 124 A B 125 C A 126 A C 127 C A 128 D A 129A B 130 A B 131 D A 132 D A 133 C A 134 B A 135 B A 136 B A 137 A B 138C A 139 B A 140 B A 141 A A 142 A B 143 B A 144 A C 145 E A 146 C A 147A A 148 A A 149 D A 150 B A 151 A A 152 C A 153 B A 154 C A 155 D A 156A A 157 D A 158 D A 159 A A 160 C A 161 D A 162 E A 163 A A 164 B A 165D A 166 A B 167 C A 168 D A 169 C A 170 E A 171 B A 172 B A 173 C A 174E A 175 A B 176 A B 177 A A 178 A A 179 D A 180 C A 181 A A 182 A A 183D A 184 D A 185 D A 186 B A 187 E A 188 D A 189 E A 190 E A 191 A B 192E A 193 B A 194 A B 195 E A 196 E A 197 C A 198 D A 199 D A 200 C A 201E A 202 D A 203 D A 204 C A 205 D A 206 E A 207 B A 208 A A 209 E A 210E A 211 D A 212 E A 213 B A 214 B A 215 A C 216 B A 217 D A 218 A C 219C A 220 D A 221 D A 222 A A 223 C A 224 A A 225 D A 226 A B 227 B A

Additional compounds not disclosed herein were also tested in the assaysdescribed in Biological Example 1 and all but one had inhibitoryactivity less than 10 micromolar for CDK2/cyclin E1. The one compoundthat had inhibitory activity greater than 10 micromolar for CDK2/cyclinE1 is shown in Table 2.

TABLE 2

1. A pharmaceutically acceptable salt of a compound selected from thegroup consisting of:

.
 2. The salt of claim 1, wherein the compound is

.
 3. The salt of claim 1, wherein the compound is

.
 4. The salt of claim 1, wherein the compound is

.
 5. The salt of claim 1, wherein the compound is

.
 6. The salt of claim 1, wherein the compound is selected from thegroup consisting of:

.
 7. The salt of claim 1, wherein the compound is

.
 8. The salt of claim 1, wherein the compound is

.
 9. The salt of claim 1, wherein the compound is

.
 10. The salt of claim 1, wherein the compound is

.
 11. The salt of claim 1, wherein the compound is

.
 12. The salt of claim 1, wherein the compound is

.
 13. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a salt of claim
 1. 14. A compound selected fromthe group consisting of:

.
 15. The compound of claim 14, wherein the compound is

.
 16. The compound of claim 14, wherein the compound is

.
 17. The compound of claim 14, wherein the compound is

.
 18. The compound of claim 14, wherein the compound is

.
 19. The compound of claim 14 selected from the group consisting of:

.
 20. The compound of claim 14, wherein the compound is

.
 21. The compound of claim 14, wherein the compound is

.
 22. The compound of claim 14, wherein the compound is

.
 23. The compound of claim 14, wherein the compound is

.
 24. The compound of claim 14, wherein the compound is

.
 25. The compound of claim 14, wherein the compound is

.
 26. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim 14.